Fused heterocyclic compounds as ion channel modulators

ABSTRACT

The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: 
     
       
         
         
             
             
         
       
     
     wherein Y, Z, n, R 1  and R 3  are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) to U.S.Provisional Application No. 61/503,980, filed on Jul. 1, 2011, theentirety of which is incorporated herein by reference.

FIELD

The present disclosure relates to novel compounds and to their use inthe treatment of various diseases, including cardiovascular diseases anddiabetes. The disclosure also relates to methods for preparation of thecompounds and to pharmaceutical compositions comprising such compounds.

BACKGROUND

The late sodium current (INaL) is a sustained component of the fast Na+current of cardiac myocytes and neurons. Many common neurological andcardiac conditions are associated with abnormal (INaL) enhancement,which contributes to the pathogenesis of both electrical and contactiledysfunction in mammals. See, for example, Pathophysiology andPharmacology of the Cardiac “Late Sodium Current”, Pharmacology andTherapeutics 119 (2008) 326-339. Accordingly, compounds that selectivelyinhibit (INaL) in mammals are useful in treating such disease states.

One example of a selective inhibitor of (INaL) is RANEXA®, a compoundapproved by the FDA for the treatment of chronic stable angina pectoris.RANEXA® has also been shown to be useful for the treatment of a varietyof cardiovascular diseases, including ischemia-reperfusion injury,arrhythmia and unstable angina, and also for the treatment of diabetes.It would be desirable to provide novel compounds that selectivelyinhibit INaL in mammals.

SUMMARY

Accordingly, typical embodiments the present disclosure provide novelcompounds that function as late sodium channel blockers. In oneembodiment, the disclosure provides compounds of Formula I:

wherein:

-   -   —Y—Z— is —C(═NR⁴)—NR²— or —C(NR⁵R⁶)═N—;    -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰,            —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),            C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,            —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰,            —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl and heterocyclyl; and            -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,                cycloalkyl, aryl, heteroaryl or heterocyclyl are                optionally substituted with one, two or three                substituents independently selected from the group                consisting of halo, —NO₂, phenyl, heterocyclyl,                heteroaryl, C₁₋₆ alkyl, cycloalkyl, —N(R²⁰)(R²²),                —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and                —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(═O)₂—    -   R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, S(O)₂—R²⁰ and                    —O—R²⁰;    -   n is 0, 1, 2, 3 or 4;    -   each R³ is independently C₁₋₆ alkyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ attached to a common carbon atom form an oxo;    -   or two R³ attached to a common or adjacent carbon atoms form a        cycloalkyl or heterocyclyl;        -   wherein said cycloalkyl or heterocyclyl are optionally            further substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁴ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and R⁴ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heteroaryl, —CN, —O—R²⁰,            —N(R²⁰)(R²²), —C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰;            and            -   wherein said C₁₋₆ alkyl or heteroaryl are optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl;    -   R⁵ is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   or R⁵ and R⁶ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN,            oxo, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰,            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, oxo, heteroaryl and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, cycloalkyl,        heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl and            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, aryloxy, —CF₃, —OCF₃,            —OCH₂CF₃, —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclyl or heteroaryl which is then        optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl;    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, stereoisomer, mixture of        stereoisomers, or tautomer thereof; provided that when R² and R⁴        join together with the atom to which they are attached to form        an optionally substituted imidazolyl, the imidazolyl it is not        directly substituted with an optionally substituted triazolyl,        or R¹ is not optionally substituted pyrazolyl, 2-pyridinonyl or        2-fluoropyridinyl.

Some embodiments provide a method of using the compounds of Formula I,IA, IB or VII, or additional Formula (s) described throughout, in thetreatment of a disease or condition in a mammal that is amenable totreatment by a late sodium channel blocker. Such diseases includecardiovascular diseases such as atrial and ventricular arrhythmias,heart failure (including congestive heart failure, diastolic heartfailure, systolic heart failure, acute heart failure), Prinzmetal's(variant) angina, stable and unstable angina, exercise induced angina,congestive heart disease, ischemia, recurrent ischemia, reperfusioninjury, myocardial infarction, acute coronary syndrome, peripheralarterial disease and intermittent claudication. Such diseases may alsoinclude diabetes and conditions related to diabetes, e.g. diabeticperipheral neuropathy. Such diseases may also include conditionsaffecting the neuromuscular system resulting in pain, seizures orparalysis. Therefore, it is contemplated that the compounds of thedisclosure and their pharmaceutically acceptable salt, ester,stereoisomer, mixture of stereoisomers and/or tautomer forms arepotentially of use as medicaments for the treatment of theaforementioned diseases.

In certain embodiments, the disclosure provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof the disclosure (e.g. a compound of Formula I, IA, IB or VII oradditional Formulas described throughout), and at least onepharmaceutically acceptable excipient.

In certain embodiments, the compound is:

I-5 3-cyclopropyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine I-63-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][l,4]oxazepine I-73-(pyrimidin-2-yl)-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-183-cyclopropyl-10-(4-(trifluoromethoxy)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine II-15-morpholino-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepineII-2N-benzyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amineII-35-(pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepineII-4N-cyclopropyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-5 N-benzyl-N-methyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-9N-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-10N-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-11N-(cyclopropylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-13 (S)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-14N-(2-(1H-imidazol-1-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-15(S)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-19N-(pyridin-2-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-20N-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-22N-(2-phenoxyethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-24N-(2-(2-chlorophenoxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-257-(4-(trifluoromethyl)phenyl)-N-((6-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-315-(4-cyclopropylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-32N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amineII-33N-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-37N-(pyrimidin-2-ylmethyl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-38(R)-tert-butyl methyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate II-39(R)-N-methyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-40 (S)-tert-butylmethyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate II-43(S)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate II-47(R)-N-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)picolinamide II-48(S)-N,N-diethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-50 (R)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-51(R)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-54N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amineII-55 5-(3-morpholinopyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-56(S)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-57 tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-585-(2-(pyridin-2-yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-605-(3-(pyridin-2-yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-611-(naphthalen-1-yloxy)-3-((R)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylamino)propan-2-ol II-62tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate II-63 (R)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylateor a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or tautomer thereof.

The inventions of this disclosure are described throughout. In addition,specific embodiments of the invention are as disclosed herein.

DETAILED DESCRIPTION 1. Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms, or from 1to 15 carbon atoms, or from 1 to 10 carbon atoms, or from 1 to 8 carbonatoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, (in some embodiments, 1, 2 or 3 substituents)        selected from the group consisting of alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl,        acylamino, acyloxy, amino, substituted amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —S(O)-alkyl,        —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,        —S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl,        —S(O)₂-heterocyclyl, —S(O)₂-aryl and —S(O)₂-heteroaryl. Unless        otherwise constrained by the definition, all substituents may        optionally be further substituted by 1, 2 or 3 substituents        chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,        aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted        amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and        —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and        n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) independently chosen from        oxygen, sulfur and NR^(a), where R^(a) is chosen from hydrogen,        alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,        heteroaryl and heterocyclyl. All substituents may be optionally        further substituted by alkyl, alkenyl, alkynyl, carboxy,        carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,        amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,        heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or        heteroaryl and n is 0, 1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms (e.g. 1, 2, 3, 4 or 5 atoms) as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents), as defined for substituted alkyl or a lower alkyl groupas defined above that is interrupted by 1, 2, 3, 4 or 5 atoms as definedfor substituted alkyl or a lower alkyl group as defined above that hasboth 1, 2, 3, 4 or 5 substituents as defined above and is alsointerrupted by 1, 2, 3, 4 or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, in some embodiments, having from 1 to 20carbon atoms (e.g. 1-10 carbon atoms or 1, 2, 3, 4, 5 or 6 carbonatoms). This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and—CH(CH₃)CH₂—), and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, in some embodiments, having 1,2, 3, 4, 5 or 6 carbon atoms.

The term “substituted alkylene” refers to an alkylene group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “aralkyloxy” refers to the group —O-aralkyl. “Optionallysubstituted aralkyloxy” refers to an optionally substituted aralkylgroup covalently linked to an optionally substituted alkylene group.Such aralkyl groups are exemplified by benzyloxy, phenylethyloxy, andthe like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds. In some embodiments, alkenyl groups includeethenyl (or vinyl, i.e. —CH═CH₂), 1-propylene (or allyl, i.e.—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂), and the like.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 20 carbon atoms (in someembodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2 or 3carbon-carbon double bonds.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds. In some embodiments, alkynyl groups includeethynyl (—C≡CH), propargyl (or propynyl, i.e. —C≡CCH₃), and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1 to 5 substituents (in some embodiments, 1, 2 or 3substituents) as defined for substituted alkyl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon, in some embodiments, having from 2 to 20 carbon atoms (insome embodiments, from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms)and having from 1 to 6 carbon-carbon triple bonds e.g. 1, 2 or 3carbon-carbon triple bonds.

The term “hydroxy” or “hydroxyl” refers to a group —OH.

The term “alkoxy” refers to the group R—O—, where R is alkyl or —Y—Z, inwhich Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyland alkynyl are as defined herein. In some embodiments, alkoxy groupsare alkyl-O— and includes, by way of example, methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term “lower alkoxy” refers to the group R—O— in which R isoptionally substituted lower alkyl. This term is exemplified by groupssuch as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,t-butoxy, n-hexyloxy, and the like.

The term “substituted alkoxy” refers to the group R—O—, where R issubstituted alkyl or —Y—Z, in which Y is substituted alkylene and Z issubstituted alkenyl or substituted alkynyl, where substituted alkyl,substituted alkenyl and substituted alkynyl are as defined herein.

The term “C₁₋₃ haloalkyl” refers to an alkyl group having from 1 to 3carbon atoms covalently bonded to from 1 to 7, or from 1 to 6, or from 1to 3, halogen(s), where alkyl and halogen are defined herein. In someembodiments, C₁₋₃ haloalkyl includes, by way of example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, 2-fluoroethyl, 3,3,3-trifluoropropyl,3,3-difluoropropyl, 3-fluoropropyl.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms, or from 3 to 10 carbon atoms, having a single cyclic ringor multiple condensed rings. Such cycloalkyl groups include, by way ofexample, single ring structures such as cyclopropyl, cyclobutyl,cyclopentyl, cyclooctyl and the like or multiple ring structures such asadamantanyl and bicyclo[2.2.1]heptanyl or cyclic alkyl groups to whichis fused an aryl group, for example indanyl, and the like, provided thatthe point of attachment is through the cyclic alkyl group.

The term “cycloalkenyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings andhaving at least one double bond and in some embodiments, from 1 to 2double bonds.

The terms “substituted cycloalkyl” and “substituted cycloalkenyl” referto cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4 or 5 substituents(in some embodiments, 1, 2 or 3 substituents), selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. The term “substituted cycloalkyl”also includes cycloalkyl groups wherein one or more of the annularcarbon atoms of the cycloalkyl group has an oxo group bonded thereto. Inaddition, a substituent on the cycloalkyl or cycloalkenyl may beattached to the same carbon atom as, or is geminal to, the attachment ofthe substituted cycloalkyl or cycloalkenyl to the 6,7-ring system.Unless otherwise constrained by the definition, all substituents mayoptionally be further substituted by 1, 2 or 3 substituents chosen fromalkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, cycloalkyl,heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) isalkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “cycloalkoxy” refers to the group cycloalkyl-O—.

The term “substituted cycloalkoxy” refers to the group substitutedcycloalkyl-O—.

The term “cycloalkenyloxy” refers to the group cycloalkenyl-O—.

The term “substituted cycloalkenyloxy” refers to the group substitutedcycloalkenyl-O—.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl and anthryl). In some embodiments, aryls include phenyl,fluorenyl, naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (in some embodiments, 1, 2 or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “heterocyclyl,” “heterocycle,” or “heterocyclic” refers to amonoradical saturated group having a single ring or multiple condensedrings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,and from 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring. In some embodiments, the heterocyclyl,”“heterocycle,” or “heterocyclic” group is linked to the remainder of themolecule through one of the heteroatoms within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (in some embodiments, 1, 2 or 3 substituents),selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino,acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. In addition, a substituent on theheterocyclic group may be attached to the same carbon atom as, or isgeminal to, the attachment of the substituted heterocyclic group to the6,7-ring system. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents chosen from alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Examplesof heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, andthe like.

The term “heterocyclooxy” refers to the group —O-heterocyclyl.

The term “heteroaryl” refers to a group comprising single or multiplerings comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within at least one ring. The term“heteroaryl” is generic to the terms “aromatic heteroaryl” and“partially saturated heteroaryl”. The term “aromatic heteroaryl” refersto a heteroaryl in which at least one ring is aromatic, regardless ofthe point of attachment. Examples of aromatic heteroaryls includepyrrole, thiophene, pyridine, quinoline, pteridine.

The term “partially saturated heteroaryl” refers to a heteroaryl havinga structure equivalent to an underlying aromatic heteroaryl which hashad one or more double bonds in an aromatic ring of the underlyingaromatic heteroaryl saturated. Examples of partially saturatedheteroaryls include dihydropyrrole, dihydropyridine, chroman,2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (in some embodiments, 1, 2 or 3 substituents) selectedfrom the group consisting alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy,amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido,cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—S(O)-alkyl, —S(O)-cycloalkyl, —S(O)-heterocyclyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)₂-alkyl, —S(O)₂-cycloalkyl, —S(O)₂-heterocyclyl,—S(O)₂-aryl and —S(O)₂-heteroaryl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents chosen from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl or heteroaryl and n is0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridylor furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazoleor benzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen or a group —Y—Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2 or 3 substituents chosen from alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkyl amine” refers to R—NH₂ in which R is optionallysubstituted alkyl.

The term “dialkyl amine” refers to R—NHR in which each R isindependently an optionally substituted alkyl.

The term “trialkyl amine” refers to NR₃ in which each R is independentlyan optionally substituted alkyl.

The term “cyano” refers to the group —CN.

The term “azido” refers to a group

The term “keto” or “oxo” refers to a group ═O.

The term “carboxy” refers to a group —C(O)—OH.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano or —S(O)_(n)R^(a), in which R^(a) is alkyl,aryl or heteroaryl and n is 0, 1 or 2.

The term “acyl” denotes the group —C(O)R, in which R is hydrogen, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl or—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl, or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the group —OC(O)—R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2 or 3 substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a),in which R^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “alkoxycarbonylamino” refers to the group —N(R^(d))C(O)OR inwhich R is alkyl and R^(d) is hydrogen or alkyl. Unless otherwiseconstrained by the definition, each alkyl may optionally be furthersubstituted by 1, 2 or 3 substituents selected from the group consistingof alkyl, alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,cycloalkyl, heterocyclyl, aryl, heteroaryl, and —S(O)_(n)R^(a), in whichR^(a) is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonylamino” refers to the group —NR^(c)(O)NRR, whereinR^(c) is hydrogen or alkyl and each R is hydrogen, alkyl, cycloalkyl,aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2 or 3 substituents selected from the group consisting of alkyl,alkenyl, alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,halogen, CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl,aryl, heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “thiol” refers to the group —SH.

The term “thiocarbonyl” refers to a group ═S.

The term “alkylthio” refers to the group —S-alkyl.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heterocyclylthio” refers to the group —S-heterocyclyl.

The term “arylthio” refers to the group —S-aryl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfoxide”refers to a group —S(O)R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl. “Substituted sulfone”refers to a group —S(O)₂R, in which R is substituted alkyl, substitutedcycloalkyl, substituted heterocyclyl, substituted aryl or substitutedheteroaryl, as defined herein.

The term “aminosulfonyl” refers to the group —S(O)₂NRR, wherein each Ris independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2 or 3substituents selected from the group consisting of alkyl, alkenyl,alkynyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,CF₃, amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl,heteroaryl, and —S(O)_(n)R^(a), in which R^(a) is alkyl, aryl orheteroaryl and n is 0, 1 or 2.

The term “hydroxyamino” refers to the group —NHOH.

The term “alkoxyamino” refers to the group —NHOR in which R isoptionally substituted alkyl.

The term “halogen” or “halo” refers to fluoro, bromo, chloro and iodo.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “loweralkyl-substituted phenyl”, where the attachment sites are not explicit,may have any available site of the lower alkyl group attached to anyavailable site of the phenyl group. In this regard, an “available site”is a site of the group at which a hydrogen of the group may be replacedwith a substituent.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,etc.) are not intended for inclusion herein. Also not included areinfinite numbers of substituents, whether the substituents are the sameor different. In such cases, the maximum number of such substituents isthree. Each of the above definitions is thus constrained by a limitationthat, for example, substituted aryl groups are limited to -substitutedaryl-(substituted aryl)-substituted aryl.

A compound of a given formula (e.g. the compound of Formula I, whichalso includes Formula IA, IB and/or VII) is intended to encompass thecompounds of the disclosure, and the pharmaceutically acceptable salts,stereoisomers, mixture of stereoisomers or tautomers of such compounds.Additionally, the compounds of the disclosure may possess one or moreasymmetric centers, and can be produced as a racemic mixture or asindividual enantiomers or diastereoisomers. The number of stereoisomerspresent in any given compound of a given formula depends upon the numberof asymmetric centers present (there are 2^(n) stereoisomers possiblewhere n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis orby resolution of the compound by conventional means. The individualstereoisomers (including individual enantiomers and diastereoisomers) aswell as racemic and non-racemic mixtures of stereoisomers areencompassed within the scope of the present disclosure, all of which areintended to be depicted by the structures of this specification unlessotherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.Isomers include stereoisomers, enantiomers and diastereomers.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

Some of the compounds exist as tautomeric isomers. Tautomeric isomersare in equilibrium with one another. For example, amide containingcompounds may exist in equilibrium with imidic acid tautomers.Regardless of which tautomer is shown, and regardless of the nature ofthe equilibrium among tautomers, the compounds are understood by one ofordinary skill in the art to comprise both amide and imidic acidtautomers. Thus, the amide containing compounds are understood toinclude their imidic acid tautomers. Likewise, the imidic acidcontaining compounds are understood to include their amide tautomers.Non-limiting examples of tautomers are shown below:

The term “therapeutically effective amount” refers to an amount that issufficient to effect treatment, as defined below, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending upon the subject and disease condition beingtreated, the weight and age of the subject, the severity of the diseasecondition, the manner of administration and the like, which can readilybe determined by one of ordinary skill in the art.

The term “polymorph” refers to different crystal structures of acrystalline compound. The different polymorphs may result fromdifferences in crystal packing (packing polymorphism) or differences inpacking between different conformers of the same molecule(conformational polymorphism).

The term “solvate” refers to a complex formed by the combining of acompound of Formula I, IA, IB or VII and a solvent.

The term “hydrate” refers to the complex formed by the combining of acompound of Formula I, IA, IB or VII and water.

The term “prodrug” refers to compounds of Formula I, IA, IB or VII thatinclude chemical groups which, in vivo, can be converted and/or can besplit off from the remainder of the molecule to provide for the activedrug, a pharmaceutically acceptable salt thereof or a biologicallyactive metabolite thereof.

Any formula or structure given herein, including Formula I, IA, IB orVII compounds, is also intended to represent unlabeled forms as well asisotopically labeled forms of the compounds. Isotopically labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the disclosure include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine and chlorine, such as but notlimited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F,³¹P, ³²P, ³⁵S, ³⁶Cl, and ¹²⁵I. Various isotopically labeled compounds ofthe present disclosure, for example those into which radioactiveisotopes such as ³H, ¹³C and ¹⁴C are incorporated. Such isotopicallylabelled compounds may be useful in metabolic studies, reaction kineticstudies, detection or imaging techniques, such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)including drug or substrate tissue distribution assays or in radioactivetreatment of patients.

The disclosure also included compounds of Formula I, IA, IB or VII inwhich from 1 to n hydrogens attached to a carbon atom is/are replaced bydeuterium, in which n is the number of hydrogens in the molecule. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half life of any compound of Formula I, IA, IB or VIIwhen administered to a mammal. See, for example, Foster, “DeuteriumIsotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well knownin the art, for example by employing starting materials in which one ormore hydrogens have been replaced by deuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I, IA, IB or VII.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

The term “treatment” or “treating” means administration of a compound ofthe invention, by or at the direction of a competent caregiver, to amammal having a disease for purposes including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl)amines, tri(substituted alkenyl)amines,cycloalkyl amines, di(cycloalkyl)amines, tri(cycloalkyl)amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines,di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substitutedcycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstitutedcycloalkenyl amines, aryl amines, diaryl amines, triaryl amines,heteroaryl amines, diheteroaryl amines, triheteroaryl amines,heterocyclic amines, diheterocyclic amines, triheterocyclic amines,mixed di- and tri-amines where at least two of the substituents on theamine are different and are selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,heterocyclic, and the like. Also included are amines where the two orthree substituents, together with the amino nitrogen, form aheterocyclic or heteroaryl group. Amines are of general structureN(R³⁰)(R³¹)(R³²), wherein mono-substituted amines have 2 of the threesubstituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen, di-substitutedamines have 1 of the three substituents on nitrogen (R³⁰, R³¹ and R³²)as hydrogen, whereas tri-substituted amines have none of the threesubstituents on nitrogen (R³⁰, R³¹ and R³²) as hydrogen. R³⁰, R³¹ andR³² are selected from a variety of substituents such as hydrogen,optionally substituted alkyl, aryl, heteroayl, cycloalkyl, cycloalkenyl,heterocyclyl and the like. The above-mentioned amines refer to thecompounds wherein either one, two or three substituents on the nitrogenare as listed in the name. For example, the term “cycloalkenyl amine”refers to cycloalkenyl-NH₂, wherein “cycloalkenyl” is as defined herein.The term “diheteroarylamine” refers to NH (heteroaryl)₂, wherein“heteroaryl” is as defined herein and so on.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine,tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Coronary diseases” or “cardiovascular diseases” refer to diseases ofthe cardiovasculature arising from any one or more than one of, forexample, heart failure (including congestive heart failure, diastolicheart failure and systolic heart failure), acute heart failure,ischemia, recurrent ischemia, myocardial infarction, arrhythmias, angina(including exercise-induced angina, variant angina, stable angina,unstable angina), acute coronary syndrome, diabetes and intermittentclaudication.

“Intermittent claudication” means the pain associated with peripheralartery disease. “Peripheral artery disease” or PAD is a type ofocclusive peripheral vascular disease (PVD). PAD affects the arteriesoutside the heart and brain. The most common symptom of PAD is a painfulcramping in the hips, thighs or calves when walking, climbing stairs orexercising. The pain is called intermittent claudication. When listingthe symptom intermittent claudication, it is intended to include bothPAD and PVD.

Arrhythmia refers to any abnormal heart rate. Bradycardia refers toabnormally slow heart rate whereas tachycardia refers to an abnormallyrapid heart rate. As used herein, the treatment of arrhythmia isintended to include the treatment of supra ventricular tachycardias suchas atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia,atrial tachycardia and the ventricular tachycardias (VTs), includingidiopathic ventricular tachycardia, ventricular fibrillation,pre-excitation syndrome and Torsade de Pointes (TdP).

2. Nomenclature

Names of compounds of the present disclosure are provided using ACD/Namesoftware for naming chemical compounds (Advanced Chemistry Development,Inc., Toronto). Other compounds or radicals may be named with commonnames or systematic or non-systematic names. The naming and numbering ofthe compounds of the disclosure is illustrated with a representativecompound of Formula I:

which is named10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.

3. Compounds

Accordingly, typical embodiments the present disclosure provide novelcompounds that function as late sodium channel blockers. In oneembodiment, the disclosure provides compounds of Formula I:

wherein:

-   -   —Y—Z— is —C(═NR⁴)—NR²— or —C(NR⁵R⁶)═N—;    -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰,            —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),            C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,            —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰,            —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl and heterocyclyl; and            -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,                cycloalkyl, aryl, heteroaryl or heterocyclyl are                optionally substituted with one, two or three                substituents independently selected from the group                consisting of halo, —NO₂, phenyl, heterocyclyl,                heteroaryl, C₁₋₆ alkyl, cycloalkyl, —N(R²⁰)(R²²),                —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and                —O—R²⁰;    -   R² is hydrogen, C₁₋₆ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(═O)₂—    -   R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, S(O)₂—R²⁰ and                    —O—R²⁰;    -   n is 0, 1, 2, 3 or 4;    -   each R³ is independently C₁₋₆ alkyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ attached to a common carbon atom form an oxo;    -   or two R³ attached to a common or adjacent carbon atoms form a        cycloalkyl or heterocyclyl;        -   wherein said cycloalkyl or heterocyclyl are optionally            further substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁴ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and R⁴ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heteroaryl, —CN, —O—R²⁰,            —N(R²⁰)(R²²), —C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰;            and            -   wherein said C₁₋₆ alkyl or heteroaryl are optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl;    -   R⁵ is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   or R⁵ and R⁶ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN,            oxo, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰,            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, oxo, heteroaryl and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, cycloalkyl,        heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl and            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, aryloxy, —CF₃, —OCF₃,            —OCH₂CF₃, —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclyl or heteroaryl which is then        optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl;    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, stereoisomer, mixture of        stereoisomers, or tautomer thereof; provided that when R² and R⁴        join together with the atom to which they are attached to form        an optionally substituted imidazolyl, the imidazolyl it is not        directly substituted with an optionally substituted triazolyl,        or R¹ is not optionally substituted pyrazolyl, 2-pyridinonyl or        2-fluoropyridinyl.

In certain embodiments, the compound of Formula I is represented byFormula IA:

wherein:

-   -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰,            —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),            C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,            —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰,            —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl and heterocyclyl; and            -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,                cycloalkyl, aryl, heteroaryl or heterocyclyl are                optionally substituted with one, two or three                substituents independently selected from the group                consisting of halo, —NO₂, phenyl, heterocyclyl,                heteroaryl, C₁₋₆ alkyl, cycloalkyl, —N(R²⁰)(R²²),                —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and                —O—R²⁰;    -   R² is hydrogen, C₁₋₆ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(═O)₂—    -   R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, S(O)₂—R²⁰ and                    —O—R²⁰;    -   n is 0, 1, 2, 3 or 4;    -   each R³ is independently C₁₋₆ alkyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ attached to a common carbon atom form an oxo;    -   or two R³ attached to a common or adjacent carbon atoms form a        cycloalkyl or heterocyclyl;        -   wherein said cycloalkyl or heterocyclyl are optionally            further substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁴ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and R⁴ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heteroaryl, —CN, —O—R²⁰,            —N(R²⁰)(R²²), —C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰;            and            -   wherein said C₁₋₆ alkyl or heteroaryl are optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, cycloalkyl,        heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl and            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, aryloxy, —CF₃, —OCF₃,            —OCH₂CF₃, —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclyl or heteroaryl which is then        optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl;    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, stereoisomer, mixture of        stereoisomers, or tautomer thereof; provided that when R² and R⁴        join together with the atom to which they are attached to form        an optionally substituted imidazolyl, the imidazolyl it is not        directly substituted with an optionally substituted triazolyl,        or R¹ is not optionally substituted pyrazolyl, 2-pyridinonyl or        2-fluoropyridinyl.

In some embodiments, R¹ is aryl;

-   -   wherein said aryl is optionally substituted with one, two or        three substituents independently selected from the group        consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,        —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶,        —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰.

In some embodiments, R¹ is aryl optionally substituted with —O—R²⁰ orC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with one,two or three halo.

In some embodiments, R¹ is aryl optionally substituted with —O—R²⁰ orC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with one,two or three halo.

In some embodiments, R¹ is

In some embodiments, R² and R⁴ join together with the atom to which theyare attached to form a heterocyclyl or heteroaryl;

-   -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl,        cycloalkyl, heteroaryl, —CN, —O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰,        —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.

In some embodiments, R² and R⁴ join together with the atom to which theyare attached to form a heterocyclyl or heteroaryl selected from thegroup consisting of

In some embodiments, n is 0.

In some embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclylor heteroaryl;

-   -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl are optionally substituted with one, two or three        substituents independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰,        O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl,        C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   n is 0; and    -   R² and R⁴ join together with the atom to which they are attached        to form a heterocyclyl or heteroaryl;    -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl,        cycloalkyl, heteroaryl, —CN, O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰,        —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.

In some embodiments, R¹ is aryl;

-   -   wherein said aryl is optionally substituted with one, two or        three substituents independently selected from the group        consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,        —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶,        —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰.    -   n is 0; and    -   R² and R⁴ join together with the atom to which they are attached        to form a heterocyclyl or heteroaryl;    -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl,        cycloalkyl, heteroaryl, —CN, O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰,        —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.

In some embodiments, R¹ is aryl optionally substituted with —O—R²⁰ orC₁₋₆ alkyl;

-   -   wherein said C₁₋₆ alkyl is optionally substituted with one, two        or three halo;    -   n is 0; and    -   R² and R⁴ join together with the atom to which they are attached        to form a heterocyclyl or heteroaryl;    -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl,        cycloalkyl, heteroaryl, —CN, O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰,        —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.

In some embodiments, R¹ is phenyl substituted with —O—CF₃ or —CF₃;

-   -   n is 0; and    -   R² and R⁴ join together with the atom to which they are attached        to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heteroaryl, —CN, —C(O)—R²⁰,            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl or heteroaryl are optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.

In some embodiments, the compound is selected from the group consistingof

I-5 3-cyclopropyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine I-63-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-73-(pyrimidin-2-yl)-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-183-cyclopropyl-10-(4-(trifluoromethoxy)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

-   -   or a pharmaceutically acceptable salt, stereoisomer, mixture of        stereoisomers, or tautomer thereof.

In certain embodiments, the compound of Formula I is represented byFormula IB:

wherein:

-   -   R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl;        -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰,            —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),            C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,            —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰,            —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl and heterocyclyl; and            -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,                cycloalkyl, aryl, heteroaryl or heterocyclyl are                optionally substituted with one, two or three                substituents independently selected from the group                consisting of halo, —NO₂, phenyl, heterocyclyl,                heteroaryl, C₁₋₆ alkyl, cycloalkyl, —N(R²⁰)(R²²),                —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and                —O—R²⁰;    -   n is 0, 1, 2, 3 or 4;    -   each R³ is independently C₁₋₆ alkyl, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl, are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, C(O)—OR²⁰,                    —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or two R³ attached to a common carbon atom form an oxo;    -   or two R³ attached to a common or adjacent carbon atoms form a        cycloalkyl or heterocyclyl;        -   wherein said cycloalkyl or heterocyclyl are optionally            further substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R⁵ is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or        heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,            heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   or R⁵ and R⁶ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heteroaryl, —CN, —O—R²⁰,            —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and            —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, oxo, heteroaryl and —O—R²⁰;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₆ alkyl, cycloalkyl,        heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl and            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo,            —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, aryloxy, —CF₃, —OCF₃,            —OCH₂CF₃, —C(O)—NH₂, aryl, cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclyl or heteroaryl which is then        optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino, —NO₂,        —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl and        cycloalkyl; and    -   each R²⁶ is independently selected from the group consisting of        hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, stereoisomer, mixture of        stereoisomers, or tautomer thereof.

In some embodiments, R¹ is aryl optionally substituted with —O—R²⁰ orC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with one,two or three halo.

In some embodiments, R¹ is aryl optionally substituted with —O—R²⁰ orC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with one,two or three halo.

In some embodiments, R¹ is

In some embodiments, n is 0.

In some embodiments, R⁵ is hydrogen or C₁₋₆ alkyl.

In some embodiments, R⁵ is hydrogen or methyl.

In some embodiments, R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl;

-   -   wherein said C₁₋₆ alkyl, heteroaryl or heterocyclyl are        optionally substituted with one, two or three substituents        independently selected from the group consisting of halo, C₁₋₆        alkyl, cycloalkyl, aryl, heteroaryl, —C(O)—R²⁰, —C(O)—OR²⁰ and        —O—R²⁰;        -   wherein said C₁₋₆ alkyl or heteroaryl are optionally further            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl or heteroaryl; and            -   wherein said C₁₋₆ alkyl is optionally further                substituted with one, two or three halo.

In some embodiments, R⁶ is selected from the group consisting of(1-methyl-1H-benzo[d]imidazol-2-yl)methyl,(1-methyl-1H-imidazol-2-yl)methyl,(1-oxo-1-pyrimidin-2-ylmethyl)pyrrolidin-3-yl,(1-oxo-tertbutoxymethyl)pyrrolidin-3-yl, (3-fluoropyridin-2-yl)methyl,(6-(trifluoromethyl)pyridin-2-yl)methyl,1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl, 1H-tetrazol-5-yl,2-(1H-imidazol-1-yl)ethyl, 2-(2-chlorophenoxy)ethyl,2-(pyridin-2-yloxy)ethyl, 2,2,2-trifluoroethyl, 2-phenoxyethyl,6-(trifluoromethyl)pyridin-2-yl, benzyl, cyclopropyl, cyclopropylmethyl,phenyl, pyridin-2-yl, pyridin-2-ylmethyl, pyrimidin-2-ylmethyl andpyrrolidin-3-yl.

In some embodiments, R⁵ and R⁶ join together with the atom to which theyare attached to form a heterocyclyl or heteroaryl;

-   -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl,        cycloalkyl, heteroaryl, —CN, —O—R²⁰, —N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and        -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            oxo, heteroaryl and —O—R²⁰.

In some embodiments, R⁵ and R⁶ join together with the atom to which theyare attached to form a heterocyclyl;

-   -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl,        cycloalkyl, hererocyclyl, heteroaryl, oxo, —O—R²⁰, —N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²⁰, and —N(R²⁰)—C(O)—OR²⁰; and        -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            oxo and —O—R²⁰.

In some embodiments, R⁵ and R⁶ join together with the atom to which theyare attached to form a heterocyclyl selected from the group consistingof

In some embodiments, R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclylor heteroaryl;

-   -   wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or        heteroaryl are optionally substituted with one, two or three        substituents independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰,        —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl,        C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   n is 0;    -   R⁵ is hydrogen or C₁₋₆ alkyl; and    -   R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;    -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or        heterocyclyl are optionally substituted with one, two or three        substituents independently selected from the group consisting of        halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,        —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or            heteroaryl are optionally further substituted with one, two            or three substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl, cycloalkyl,            aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and            -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                heterocyclyl or heteroaryl are optionally further                substituted with one, two or three substituents                independently selected from the group consisting of                hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                —C(O)—OR²⁰;    -   or R⁵ and R⁶ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;    -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of halo, C₁₋₆ alkyl,        cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —O—R²⁰,        —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and        —C(O)—OR²⁰; and        -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            oxo, heteroaryl and —O—R²⁰.

In some embodiments, R¹ is aryl;

-   -   wherein said aryl is optionally substituted with one, two or        three substituents independently selected from the group        consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,        —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²),        —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶,        —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl and        heterocyclyl; and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   n is 0;    -   R⁵ is hydrogen or C₁₋₆ alkyl; and    -   R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   or R⁵ and R⁶ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo,            —CN, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰,            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, oxo, heteroaryl and —O—R²⁰.

In some embodiments, R¹ is aryl optionally substituted with —O—R²⁰ orC₁₋₆ alkyl; and

-   -   wherein said C₁₋₆ alkyl is optionally substituted with one, two        or three halo;    -   n is 0;    -   R⁵ is hydrogen or C₁₋₁₅ alkyl; and    -   R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   or R⁵ and R⁶ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo,            —CN, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰,            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, oxo, heteroaryl and —O—R²⁰.

In some embodiments, R¹ is phenyl substituted with —O—CF₃ or —CF₃;

-   -   n is 0;    -   R⁵ is hydrogen or C₁₋₁₅ alkyl; and    -   R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or            heteroaryl are optionally substituted with one, two or three            substituents independently selected from the group            consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,            —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰;    -   or R⁵ and R⁶ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            C₁₋₆ alkyl, cycloalkyl, hetercyclyl, aryl, heteroaryl, oxo,            —CN, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰,            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₆ alkyl or heterocyclyl is optionally                substituted with one, two or three substituents                independently selected from the group consisting of                halo, oxo, heteroaryl and —O—R²⁰.

In some embodiments, the compound is selected from the group consistingof:

II-15-morpholino-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepineII-2N-benzyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amineII-35-(pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepineII-4N-cyclopropyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-5 N-benzyl-N-methyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-9N-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-10N-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-11N-(cyclopropylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-13 (S)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-14N-(2-(1H-imidazol-1-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-15(S)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-19N-(pyridin-2-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-20N-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-22N-(2-phenoxyethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-24N-(2-(2-chlorophenoxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-257-(4-(trifluoromethyl)phenyl)-N-((6-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-315-(4-cyclopropylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-32N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amineII-33N-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine II-37N-(pyrimidin-2-ylmethyl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-38(R)-tert-butyl methyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate II-39(R)-N-methyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-40 (S)-tert-butylmethyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate II-43(S)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate II-47(R)-N-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)picolinamide II-48(S)-N,N-diethyl-1-(7-(4-(trifluoromemyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-50(R)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-51(R)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-54N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amineII-55 5-(3-morpholinopyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-56(S)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-57 tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-585-(2-(pyridin-2-yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-605-(3-(pyridin-2-yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-611-(naphthalen-1-yloxy)-3-((R)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylamino)propan-2-ol II-62tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate II-63 (R)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate

-   -   or a pharmaceutically acceptable salt, stereoisomer, mixture of        stereoisomers, or tautomer thereof.

4. Alternative Embodiments

In alternative embodiments, the compound of Formula I is represented byFormula VII:

wherein:

-   -   n is 0, 1, 2 or 3:    -   each R¹⁰ is independently selected from the group consisting of        halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰,        —C(O)—OR²⁰, —N(R²⁰)(R²²), —C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,        —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰,        —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        cycloalkyl, aryl, heteroaryl and heterocyclyl and heterocyclyl;        and        -   wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally            substituted with one, two or three substituents            independently selected from the group consisting of halo,            —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl,            cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,            —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   R² is hydrogen, C₁₋₁₅ alkyl, —C(O)—R²⁰, —C(O)—OR²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—    -   R²⁰, cycloalkyl, aryl, heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or            heterocyclyl are optionally substituted with one, two or            three substituents independently selected from the group            consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂,            cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),            —C(O)—OR²⁰, —C(O)—R²⁰, —C(O)—N(R²⁰)(R²²), —CN, oxo and            —O—R²⁰;            -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl                or heteroaryl are optionally further substituted with                one, two or three substituents independently selected                from the group consisting of halo, —NO₂, C₁₋₆ alkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, S(O)₂—R²⁰ and                    —O—R²⁰;    -   R⁵ is hydrogen, C₁₋₁₅ alkyl, C₁₋₄ alkoxy, —C(O)—O—R²⁶,        —C(O)—N(R²⁶)(R²⁸), —N(R²⁰)—S(═O)₂—R²⁰, cycloalkyl, aryl,        heteroaryl or heterocyclyl;        -   wherein said C₁₋₁₅ alkyl is optionally substituted with one,            two or three substituents independently selected from the            group consisting of halo, —NO₂, cycloalkyl, aryl,            heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—OR²⁰,            —C(O)—R²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;            -   wherein said cycloalkyl, aryl, heterocyclyl or                heteroaryl are optionally further substituted with one,                two or three substituents independently selected from                the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,                cycloalkyl, aryl, heterocyclyl, heteroaryl,                —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²),                —CN and —O—R²⁰; and                -   wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,                    heterocyclyl or heteroaryl are optionally further                    substituted with one, two or three substituents                    independently selected from the group consisting of                    hydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰,                    —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;    -   or R² and R⁵ can join together with the atom to which they are        attached to form a heterocyclyl or heteroaryl;        -   wherein said heterocyclyl or heteroaryl is optionally            substituted with one, two or three substituents            independently selected from the group consisting of C₁₋₁₅            alkyl, cycloalkyl, heteroaryl, —O—R²⁰, —N(R²⁰)(R²²),            —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and            -   wherein said C₁₋₁₅ alkyl is optionally substituted with                one, two or three substituents independently selected                from the group consisting of halo and heteroaryl;    -   R²⁰ and R²² are in each instance independently selected from the        group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and        -   wherein the C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,            cycloalkyl, heterocyclyl, aryl, and heteroaryl are            optionally substituted with one, two or three substituents            independently selected from the group consisting of            hydroxyl, halo, C₁₋₄ alkyl, acylamino, —NO₂, —SO₂R²⁶, —CN,            C₁₋₃ alkoxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl,            cycloalkyl and heteroaryl;            -   wherein said heteroaryl is optionally further                substituted with C₁₋₄ alkyl or cycloalkyl; or    -   when R²⁰ and R²² are attached to a common nitrogen atom R²⁰ and        R²² may join to form a heterocyclic or heteroaryl ring which is        then optionally substituted with one, two or three substituents        independently selected from the group consisting of hydroxyl,        halo, C₁₋₄ alkyl, aralkyl, aryl, aryloxy, aralkyloxy, acylamino,        —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl        and cycloalkyl;    -   R²⁵ is in each instance independently a covalent bond or C₁₋₃        alkylene optionally substituted with one or two C₁₋₃ alkyl        groups; and    -   R²⁶ and R²⁸ are in each instance independently selected from the        group consisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl;        and        -   wherein the C₁₋₄ alkyl, aryl and cycloalkyl may be further            substituted with from 1 to 3 substituents independently            selected from the group consisting of hydroxyl, halo, C₁₋₄            alkoxy, —CF₃ and —OCF₃;    -   or a pharmaceutically acceptable salt, ester, hydrate, solvate,        stereoisomer, mixture of stereoisomers, tautomer, polymorph        and/or prodrug thereof.

In some embodiments, when R² and R⁵ join together with the atom to whichthey are attached to form an optionally substituted imidazolyl, theimidazolyl it is not directly substituted with an optionally substitutedtriazolyl, or R¹ is not optionally substituted pyrazolyl, 2-pyridinonylor 2-fluoropyridinyl.

In some embodiments, R² and R⁵ are joined together with the atom towhich they are attached to form a heterocyclyl or heteroaryl;

-   -   wherein said heterocyclyl or heteroaryl is optionally        substituted with one, two or three substituents independently        selected from the group consisting of C₁₋₁₅ alkyl, cycloalkyl        and heteroaryl.

In some embodiments, R² and R⁵ are joined together with the atom towhich they are attached to form

In some embodiments, R¹⁰ is 4-trifluoromethyl.

In some embodiments, the compound is selected from the group consistingof

-   3-cyclopropyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine;-   3-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine;    and-   3-(pyrimidin-2-yl)-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine;    or a pharmaceutically acceptable salt, ester, hydrate, solvate,    stereoisomer, mixture of stereoisomers, tautomer, polymorph and/or    prodrug thereof.

5. Further Embodiments

In some embodiments, the compounds provided by the present disclosureare effective in the treatment of conditions or diseases known torespond to administration of late sodium channel blockers, including butnot limited to cardiovascular diseases such as atrial and ventriculararrhythmias, including atrial fibrillation, Prinzmetal's (variant)angina, stable angina, unstable angina, ischemia and reperfusion injuryin cardiac, kidney, liver and the brain, exercise induced angina,pulmonary hypertension, congestive heart disease including diastolic andsystolic heart failure, and myocardial infarction. In some embodiments,compounds provided by the present disclosure which function as latesodium channel blockers may be used in the treatment of diseasesaffecting the neuromuscular system resulting in pain, itching, seizures,or paralysis, or in the treatment of diabetes or reduced insulinsensitivity, and disease states related to diabetes, such as diabeticperipheral neuropathy.

Certain compounds of the disclosure may also possess a sufficientactivity in modulating neuronal sodium channels, i.e., Na_(v) 1.1., 1.2,1.3, 1.5, 1.7, and/or 1.8, and may have appropriate pharmacokineticproperties such that they may be active with regard to the centraland/or peripheral nervous system. Consequently, some compounds of thedisclosure may also be of use in the treatment of epilepsy or pain oritching or heachache of a neuropathic origin.

In one embodiment, this disclosure provides a method of treating adisease state in a mammal that is alleviable by treatment with an agentcapable of reducing late sodium current, comprising administering to amammal in need thereof a therapeutically effective dose of a compound ofFormula I, IA, IB or VII or other formulas or compounds disclosedherein. In another embodiment, the disease state is a cardiovasculardisease selected from one or more of atrial and ventricular arrhythmias,heart failure (including congestive heart failure, diastolic heartfailure, systolic heart failure, acute heart failure), Prinzmetal's(variant) angina, stable and unstable angina, exercise induced angina,congestive heart disease, ischemia, recurrent ischemia, reperfusioninjury, myocardial infarction, acute coronary syndrome, peripheralarterial disease, pulmonary hypertension, and intermittent claudication.

In another embodiment, the disease state is diabetes or diabeticperipheral neuropathy. In a further embodiment, the disease stateresults in one or more of neuropathic pain, epilepsy, heachache,seizures, or paralysis.

In one embodiment, this disclosure provides a method of treatingdiabetes in a mammal, comprising administering to a mammal in needthereof a therapeutically effective dose of a compound of Formula I, IA,IB or VII or other formulas or compounds disclosed herein. Diabetesmellitus is a disease characterized by hyperglycemia; altered metabolismof lipids, carbohydrates and proteins; and an increased risk ofcomplications from vascular disease. Diabetes is an increasing publichealth problem, as it is associated with both increasing age andobesity.

There are two major types of diabetes mellitus: 1) Type I, also known asinsulin dependent diabetes (IDDM) and 2) Type II, also known as insulinindependent or non-insulin dependent diabetes (NIDDM). Both types ofdiabetes mellitus are due to insufficient amounts of circulating insulinand/or a decrease in the response of peripheral tissue to insulin.

Type I diabetes results from the body's failure to produce insulin, thehormone that “unlocks” the cells of the body, allowing glucose to enterand fuel them. The complications of Type I diabetes include heartdisease and stroke; retinopathy (eye disease); kidney disease(nephropathy); neuropathy (nerve damage); as well as maintenance of goodskin, foot and oral health.

Type II diabetes results from the body's inability to either produceenough insulin or the cells inability to use the insulin that isnaturally produced by the body. The condition where the body is not ableto optimally use insulin is called insulin resistance. Type II diabetesis often accompanied by high blood pressure and this may contribute toheart disease. In patients with type II diabetes mellitus, stress,infection, and medications (such as corticosteroids) can also lead toseverely elevated blood sugar levels. Accompanied by dehydration, severeblood sugar elevation in patients with type II diabetes can lead to anincrease in blood osmolality (hyperosmolar state). This condition canlead to coma.

It has been suggested that ranolazine (RANEXA®, a selective inhibitor ofINaL) may be an antidiabetic agent that causes β-cell preservation andenhances insulin secretion in a glucose-dependent manner in diabeticmice (see, Y. Ning et al. J Pharmacol Exp Ther. 2011, 337(1), 50-8).Therefore it is contemplated that the compounds of Formula I, IA, IB orVII or other formulas or compounds disclosed herein can be used asantidiabetic agents for the treatment of diabetes.

6. Pharmaceutical Compositions and Administration

Compounds provided in accordance with the present disclosure are usuallyadministered in the form of pharmaceutical compositions. This disclosuretherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present disclosure maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present disclosure. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present disclosure in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof. Preferably, for parenteral administration, sterileinjectable solutions are prepared containing a therapeutically effectiveamount, e.g., 0.1 to 700 mg, of a compound described herein. It will beunderstood, however, that the amount of the compound actuallyadministered usually will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

Oral administration is another route for administration of compounds inaccordance with the disclosure. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the disclosure can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present disclosure employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present disclosure incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g, or alternatively, or 100 mg to 500 mg, of a compounddescribed herein, and for parenteral administration, preferably from 0.1mg to 700 mg, or alternatively, 0.1 mg to 100 mg, of a compound acompound described herein. It will be understood, however, that theamount of the compound actually administered usually will be determinedby a physician, in the light of the relevant circumstances, includingthe condition to be treated, the chosen route of administration, theactual compound administered and its relative activity, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present disclosure may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

Combination Therapy

Patients being treated by administration of the late sodium channelblockers of the disclosure often exhibit diseases or conditions thatbenefit from treatment with other therapeutic agents. These diseases orconditions can be of cardiovascular nature or can be related topulmonary disorders, metabolic disorders, gastrointestinal disorders andthe like. Additionally, some coronary patients being treated byadministration of the late sodium channel blockers of the disclosureexhibit conditions that can benefit from treatment with therapeuticagents that are antibiotics, analgesics, and/or antidepressants andanti-anxiety agents.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the late sodium channel blockers of thedisclosure with other therapeutic agents include, without limitation,angina including stable angina, unstable angina (UA), exercised-inducedangina, variant angina, arrhythmias, intermittent claudication,myocardial infarction including non-STE myocardial infarction (NSTEMI),pulmonary hypertension including pulmonary arterial hypertension, heartfailure including congestive (or chronic) heart failure and diastolicheart failure and heart failure with preserved ejection fraction(diastolic dysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the late sodium channel blockers of thedisclosure with therapeutic agents suitable for treating cardiovascularrelated conditions allows enhancement in the standard of care therapythe patient is currently receiving. In some embodiments, the late sodiumchannel blockers of the disclosure are co-administered with ranolazine(RANEXA®).

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral®),atenolol (Tenormin®), betaxolol (Kerlone®),bisoprolol/hydrochlorothiazide (Ziac®), bisoprolol (Zebeta®), carteolol(Cartrol®), esmolol (Brevibloc®), labetalol (Normodyne®, Trandate®),metoprolol (Lopressor®, Toprol® XL), nadolol (Corgard®), propranolol(Inderal®), sotalol (Betapace®), and timolol (Blocadren®).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc®, Lotrel®),bepridil (Vascor®), diltiazem (Cardizem®, Tiazac®), felodipine(Plendil®), nifedipine (Adalat®, Procardia®), nimodipine (Nimotop®),nisoldipine (Sular®), verapamil (Calan®, Isoptin®, Verelan®), andnicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn®), furosemide (Lasix®), bumetanide (Bumex®),spironolactone (Aldactone®), and eplerenone (Inspra®).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin®),captopril (Capoten®), enalapril (Vasotec®), fosinopril (Monopril®),lisinopril (Prinivil®, Zestril®), moexipril (Univasc®), perindopril(Aceon®), quinapril (Accupril®), ramipril (Altace®), and trandolapril(Mavik®).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(Plavix®), prasugrel (Effient®), dipyridamole, cilostazol, persantinesulfinpyrazone, dipyridamole, indomethacin, and glycoprotein llb/lllainhibitors, such as abciximab, tirofiban, and eptifibatide(Integrelin®). Beta blockers and calcium channel blockers also have aplatelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax®), warfarin (Coumadin®), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interest(see U.S. Patent Application Publication No. 2010/0056536 and U.S.Patent Application Publication No. 2011/0183990, the entirety of whichare incorporated herein).

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot formation.Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress®), doxazosin mesylate(Cardura®), prazosin hydrochloride (Minipress®), prazosin, polythiazide(Minizide®), and terazosin hydrochloride (Hytrin®); beta-adrenergicantagonists, such as propranolol (Inderal®), nadolol (Corgard®), timolol(Blocadren®), metoprolol (Lopressor®), and pindolol (Visken®); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride(Catapres®), clonidine hydrochloride and chlorthalidone (Clorpres®,Combipres®), guanabenz Acetate (Wytensin®), guanfacine hydrochloride(Tenex®), methyldopa (Aldomet®), methyldopa and chlorothiazide(Aldoclor®), methyldopa and hydrochlorothiazide (Aldoril®); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne®,Trandate®), carvedilol (Coreg®); adrenergic neuron blocking agents, suchas guanethidine (Ismelin®), reserpine (Serpasil®); central nervoussystem-acting antihypertensives, such as clonidine (Catapres®),methyldopa (Aldomet®), guanabenz (Wytensin®); anti-angiotensin IIagents; ACE inhibitors, such as perindopril (Aceon®) captopril(Capoten®), enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®);angiotensin-II receptor antagonists, such as candesartan (Atacand®),eprosartan (Teveten®), irbesartan (Avapro®), losartan (Cozaar®),telmisartan (Micardis®), valsartan (Diovan®); calcium channel blockers,such as verapamil (Calan®, Isoptin®), diltiazem (Cardizem®), nifedipine(Adalat®, Procardia®); diuretics; direct vasodilators, such asnitroprusside (Nipride®), diazoxide (Hyperstat® IV), hydralazine(Apresoline®), minoxidil (Loniten®), verapamil; and potassium channelactivators, such as aprikalim, bimakalim, cromakalim, emakalim,nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip®), ciprofibrate (Modalim®), and statins,such as atorvastatin (Lipitor®), fluvastatin (Lescol®), lovastatin(Mevacor®, Altocor®), mevastatin, pitavastatin (Livalo®, Pitava®)pravastatin (Lipostat®), rosuvastatin (Crestor®), and simvastatin(Zocor®).

In this disclosure, the patient presenting with an acute coronarydisease event often suffers from secondary medical conditions such asone or more of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient a compound as disclosed herein (e.g., Formula I, IA, IBor VII) in combination with at least one therapeutic agent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire®, Bricanyl®), albuterol(Proventil®), salmeterol (Serevent®, Serevent Diskus®), theophylline,ipratropium bromide (Atrovent®), tiotropium (Spiriva®),methylprednisolone (Solu-Medrol®, Medrol®), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix®),lansoprazole (Prevacid®), esomeprazole (Nexium®), omeprazole(Prilosec®), rabeprazole; H2 blockers, such as cimetidine (Tagamet®),ranitidine (Zantac®), famotidine (Pepcid®), nizatidine (Axid®);prostaglandins, such as misoprostol (Cytotec®); sucralfate; andantacids.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with a compound as disclosed herein (e.g., FormulaI, IA, IB or VII).

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include β-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricef®), cephalexin (Keflex®), cephradine (Velosef®), cefaclor(Ceclor®), cefuroxime axtel (Ceftin®), cefprozil (Cefzil®), loracarbef(Lorabid®), cefixime (Suprax®), cefpodoxime proxetil (Vantin®),ceftibuten (Cedax®), cefdinir (Omnicef®), ceftriaxone (Rocephin®),carbapenems, and monobactams; tetracyclines, such as tetracycline;macrolide antibiotics, such as erythromycin; aminoglycosides, such asgentamicin, tobramycin, amikacin; quinolones such as ciprofloxacin;cyclic peptides, such as vancomycin, streptogramins, polymyxins;lincosamides, such as clindamycin; oxazolidinoes, such as linezolid; andsulfa antibiotics, such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe abilty of the late sodium channel blockers of the disclosure totreat neuropathic pain via inhibition of the Na_(v) 1.7 and 1.8 sodiumchannels, combination with analgesics are particularly invisioned. SeeU.S. Patent Application Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillers. Examples of antidepressant and anti-anxiety agents includebenzodiazepines, such as diazepam, lorazepam, and midazolam;enzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft®, Lustral®, Apo-Sertral®, Asentra®,Gladem®, Serlift®, Stimuloton®); escitalopram (Lexapro®, Cipralex®);fluoxetine (Prozac®, Sarafem®, Fluctin®, Fontex®, Prodep®, Fludep®,Lovan®); venlafaxine (Effexor® XR, Efexor®); citalopram (Celexa®,Cipramil®, Talohexane®); paroxetine (Paxil®, Seroxat®, Aropax®);trazodone (Desyrel®); amitriptyline (Elavil®); and bupropion(Wellbutrin®, Zyban®).

Accordingly, one aspect of the disclosure provides for a compositioncomprising the late sodium channel blockers of the disclosure and atleast one therapeutic agent. In an alternative embodiment, thecomposition comprises the late sodium channel blockers of the disclosureand at least two therapeutic agents. In further alternative embodiments,the composition comprises the late sodium channel blockers of thedisclosure and at least three therapeutic agents, the late sodiumchannel blockers of the disclosure and at least four therapeutic agents,or the late sodium channel blockers of the disclosure and at least fivetherapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the late sodium channel blockers of thedisclosure and therapeutic agent or agents, essentially contemporaneousadministration of more than one formulation comprising the late sodiumchannel blocker of the disclosure and therapeutic agent or agents, andconsecutive administration of a late sodium channel blocker of thedisclosure and therapeutic agent or agents, in any order, whereinpreferably there is a time period where the late sodium channel blockerof the disclosure and therapeutic agent or agents simultaneously exerttheir therapeutic affect.

7. Synthesis of Example Compounds

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described herein,e.g. compounds having structures described by one or more of Formula I,IA, IB or VII or other formulas or compounds disclosed herein, may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers.

General Syntheses

Typical embodiments of compounds in accordance with the presentdisclosure may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present disclosure, inspection of the structure of the compound tobe synthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

Synthetic Reaction Parameters

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts (1999) Protecting Groups inOrganic Synthesis, 3rd Edition, Wiley, New York, and references citedtherein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5^(th) Edition,2001), and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula I

The compounds of Formula I are typically prepared by first providing themolecular core 1-1 and then attaching the desired —R¹ substituent usingsuitable coupling conditions (e.g., Suzuki coupling). This process isshow below in Scheme 1 for the synthesis of a compound of Formula I.

In general, a halogenated compound of formula 1-1, in this case abrominated compound, is reacted with an appropriately substitutedboronic acid derivative of formula R¹—B(OH)₂ or a boronic ester thereof,in an inert solvent, for example aqueous N,N-dimethylformamide, in thepresence of a mild base, for example potassium carbonate or sodiumbicarbonate. The reaction is typically conducted in the presence of ametal catalyst with an appropriate ligand, for exampledichlorobis(triphenylphosphine) palladium(II), at a temperature of about120-170° C., for about 10 minutes to about 1 hour or at a lowertemperature, ie., 90-110° C. for 2 to 5 days. When the reaction issubstantially complete, the product of Formula I is isolated byconventional means.

Optional Core Synthesis

In certain embodiments, the core may be synthesized before or afteraddition of the —R¹ substitutent (Scheme 2). For example, such analternative route for the synthesis of compounds of formula 2-3 and 2-4(i.e., Formulas IA and IB, respectively) is shown in Scheme 2, below.

In one embodiment, compounds of Formula 2-2 can be provided from theamination of compounds of Formula 2-1 with a amine of formula NH₂—R⁴.

The R² moiety may be coupled to compounds of Formula 2-2 undersubstitution reaction conditions with an appropriate reagent of formulaLG-R² (where LG is a leaving group such as a halo, hydroxyl, alkoxy, orthe like) to afford compounds of Formula 2-3. Typical substitutionreaction conditions include the presence of a base, such as ssiumcarbonate, sodium bicarbonate, triethylamine, and the like, in a polaraprotic solvent, such as N,N-dimethylformamide, and optionally anelevated temperature of about 100-150° C. or in a microwave.

In one embodiment, compounds of Formula 2-4 can be provided from theamination of compounds of Formula 2-1 with a amine of formula NH(R⁵R⁶).

It will also be appreciated that the addition of any substituent mayresult in the production of a number of isomeric products any or all ofwhich may be isolated and purified using conventional techniques.

The following examples are included to demonstrate preferred embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the disclosure, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe disclosure.

List of Abbreviations and Acronyms Abbreviation Meaning ° C. DegreeCelcius anal Analytical ATP Adenosine-5′-triphosphate ATX II Anemoniasulcata toxin ACN Acetonitrile CHO Chinese hamster ovary d Doublet ddDoublet of doublets DIPEA N,N-diisopropylethylamine DMFDimethylformamide DMSO Dimethylsulfoxide ECF Extracellular fluid EDTAEthylenediaminetetraacetic acid EGTA Ethylene glycol tetraacetic acid gGrams HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid) hERGhuman Ether-à-go-go Related Gene HPLC High-performance liquidchromatography h Hours Hz Hertz IC₅₀ The half maximal inhibitoryconcentration IMR-32 Human neuroblastoma cell line J Coupling constantKg Kilogram kHz Kilohertz M Molar m Multiplet m/z mass-to-charge ratioM+ Mass peak M + H Mass peak plus hydrogen mg Milligram MHz Megahertzmin/m Minute ml/mL Milliliter mM Millimolar mmol Millimole nmol NanomolenM Nanomolar mOsmol Milliosmole MS Mass spectroscopy ms Millisecond mVMillivolt mw Microwave mol Mole NMR Nuclear magnetic resonance pAPicoamps PPTS Pyridinium p-toluenesulfonate q.s. Quantity sufficient toachieve a stated function Rf Retention factor s Second s Singlet SEMStandard error of the mean TB Tonic Block TEA Triethylamine TFATrifluoroacetic acid THF Tetrahydrofuran TTX Tetrodotoxin UDB UseDependent Block WT Wild type δ Chemical shift μg Microgram μL/μlMicroliter μM Micromolar μm Micrometer

EXAMPLES Example 110-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-1)

A solution of7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one(3.6 g, 11.7 mmol) and phosphorous pentachloride (2.56 g, 12.3 mmol) intoluene (80 mL) was refluxed for 2 hours. The reaction mixture wasconcentrated to yield5-chloro-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepineand used in subsequent steps without further purification.

A solution of5-chloro-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(11.7 mmol) in 2,2-dimethoxyethanamine (20 mL) was heated at 100° C. for1 hour. The reaction mixture was concentrated to give(Z)-2,2-dimethoxy-N-(7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-ylidene)ethanamineas an oil. The crude material was dissolved in toluene (80 mL) and PPTS(6.0 g) was added and the mixture was refluxed for 5 h. The reactionmixture partitioned between ethyl acetate and brine and filtered throughcelite. The organic layer was dried with sodium sulfate and concentratedbefore being purified by silica gel chromatography (Rf=0.15 in 2:1hexanes/ethyl acetate) to give10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineas a white solid (2.3 g, 60% over three steps). C₁₈H₁₃F₃N₂O×TFA. 331.1(M+1). ¹H NMR (DMSO) δ 8.53 (d, J=2.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 2H),7.91 (dd, J=8.0, 2.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.77 (d, J=12.0Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 4.65 (m, 4H). ¹⁹F NMR (DMSO) δ −59.21(s, 3F).

Example 210-(4-(trifluoromethoxy)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-2)

Compound I-2 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₈H₁₃F₃N₂O₂×TFA. 347.1 (M+1).¹H NMR (DMSO) δ 8.45 (d, 2.0 Hz, 1H), 7.86 (m, 3H), 7.76 (d, J=12.0 Hz,2H), 7.51 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 1H), 4.65 (m, 4H). ¹⁹FNMR (DMSO) δ −57.30 (s, 3F).

Example 310-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine(Compound I-3)

A solution of 7-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (2 g,8.3 mmol) P₂S₅ (4.4 g, 10.0 mmol) acetonitrile (40 mL) and triethylamine(20 mL) was refluxed for 4 h. The mixture was concentrated and dissolvedin dichloromethane before being washed three times with water. Theorganic layer was dried with sodium sulfate and concentrated beforebeing purified by silica gel chromatography (Rf=0.35 in 2:1hexanes/ethyl acetate) to give7-bromo-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-thione as yellow powder(1.3 g, 61%).

A solution of 7-bromo-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-thione(500 mg, 1.94 mmol), anhydrous hydrazine (0.3 mL) and THF was refluxedfor 1 h. The reaction was concentrated and the crude hydrazonamide wastaken on without further purification. A solution of7-bromo-5-hydrazono-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine in formicacid was reluxed for 1 h. The mixture was concentrated and subjected totypical Suzuki reaction conditions followed by preperative HPLC to giveCompound I-3. C₁₇H₁₂F₃N₃O. 332.1 (M+1).

Example 43-cyclopropyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine(Compound I-5)

Compound I-5 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₀H₁₆F₃N₃O. 372.1 (M+1).

Example 53-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-6)

Compound I-6 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁₅F₃N₂O. 345.1 (M+1).

Example 63-(pyrimidin-2-yl)-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-7)

Compound I-7 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₂H₁₅F₃N₄O. 409.1 (M+1).

Example 73-benzyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-11)

Compound I-11 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₅H₁₉F₃N₂O. 421.1 (M+1).

Example 82-chloro-3-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-14)

Compound I-14 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁₄ClF₃N₂O. 379.4 (M+1).

Example 91-(10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-3-yl)ethanone(Compound I-15)

Compound I-15 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₀H₁₅F₃N₂O. 373.1 (M+1).

Example 103-methyl-10-(4-(trifluoromethoxy)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-17)

Compound I-17 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁₅F₃N₂O₂. 361.1 (M+1).

Example 113-cyclopropyl-10-(4-(trifluoromethoxy)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-18)

Compound II-5 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₁₇F₃N₂O₂. 387.1 (M+1).

Example 122-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-19)

Compound I-19 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁₅F₃N₂O. 345.1 (M+1).

Example 132-cyclopropyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-20)

Compound II-5 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₁H₁₇F₃N₂O. 371.1 (M+1).

Example 145-morpholino-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-1)

Compound II-1 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₀H₁₉F₃N₂O₂. 377.1 (M+1).

Example 15N-benzyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-2)

Compound II-2 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₃H₁₉F₃N₂O. 397.1 (M+1).

Example 165-(pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-3)

Compound II-3 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₀H₁₉F₃N₂O. 361.1 (M+1).

Example 17N-cyclopropyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-4)

Compound II-4 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₁₉H₁₇F₃N₂O. 347.1 (M+1).

Example 18N-benzyl-N-methyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-5)

Compound II-5 was prepared according to the Examples disclosed hereinusing the appropriate starting materials. C₂₄H₂₁F₃N₂O. 411.1 (M+1).

Example 19(S)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-15)

To a anhydrous DMF solution (3 mL) of the compound A (65 mg, 0.20 mmol)and (S)-N,N-dimethylpyrrolidin-3-amine (69 mg, 0.60 mmol) was addedHunig's base (0.30 mL, 1.68 mmol) with stir. The reaction mixture wassubjected to Biotage microwave heating at 120° C. for 20 min. Theresulting mixture was filtered, concentrated in vaccuo, and subjected toGilson preparative HPLC, eluting with a gradient of ACN in H₂O (5% to95%) to afford Compound II-15 (45 mg, 0.11 mmol, 55%). LCMS m/z 404.2(M+H), anal HPLC 100% in purity. ¹H NMR (400 MHz; DMSO-d6) δ 8.72 (s,2H); 7.93 (m, 4H); 7.82 (d, J=8.1 Hz, 2H); 7.31 (d, J=8.2 Hz, 1H); 4.35(m, 2H); 3.61-3.33 (m, 5H); 3.16 (s, 1H); 2.77 (m, 1H); 2.15 (s, 6H);2.07 (m, 1H); 1.79 (m, 1H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −61.42 (s, 3F).

Example 20N-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-7)

Compound II-7 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 21N-cyclopropyl-N-methyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-8)

Compound II-8 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 22N-((3-fluoropyridin-2-Amethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-9)

Compound II-9 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 416.1, M+H.

Example 23 tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)azetidin-3-ylcarbamate(Compound II-12)

Compound II-12 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 24 (R)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate(Compound II-50)

Compound II-50 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 476.1, M+H).

Example 25 (S)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate(Compound II-13)

Compound II-7 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 476.1, M+H).

Example 26N-(2-(1H-imidazol-1-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-14)

Compound II-14 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 401.1, M+H.

Example 27(S)-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)methanol(Compound II-16)

Compound II-16 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 28N-((1-methyl-1H-imidazol-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-17)

Compound II-17 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 291-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)azetidin-3-amine(Compound II-18)

Compound II-18 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 305-(4,4-difluoropiperidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-21)

Compound II-21 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 311-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ol(Compound II-23)

Compound II-23 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 32N-(2-(2-chlorophenoxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-24)

Compound II-24 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 461.1, M+H.

Example 337-(4-(trifluoromethyl)phenyl)-N-((6-(trifluoromethyl)pyridin-2-Amethyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-25)

Compound II-25 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials MS m/z 466.1, M+H.

Example 34N-(1H-tetrazol-5-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-26)

Compound II-26 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 375.1, M+H.

Example 357-(4-(trifluoromethyl)phenyl)-N-(6-(trifluoromethyl)pyridin-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-27)

Compound II-27 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 365-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-28)

Compound II-28 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 37(R)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-51)

Compound II-51 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 404.1, M+H.

Example 38N-(2,2,2-trifluoroethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-29)

Compound II-29 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 391-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-2-one(Compound II-30)

Compound II-30 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 405-(4-methylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-52)

Compound II-52 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 41 (S)-tert-butyl3-methyl-4-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)piperazine-1-carboxylate(Compound II-53)

Compound II-7 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 425-(4-cyclopropylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-31)

Compound II-31 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 416.1, M+H.

Example 43N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-54)

Compound II-54 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 383.1, M+H.

Example 445-(3-morpholinopyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-55)

Compound II-55 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 45(S)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-56)

Compound II-56 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 46 tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate(Compound II-57)

Compound II-7 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 476.1, M+H.

Example 475-(2-(pyridin-2-yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-58)

Compound II-58 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 48N-(pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-59)

Compound II-59 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 49N-(1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-34)

Compound II-34 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 50pyrimidin-2-yl(3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidin-1-yl)methanone(Compound II-35)

Compound II-35 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 515-(3-(pyridin-2-yflpyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-60)

Compound II-7 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 438.1, M+H.

Example 525-(1,3′-bipyrrolidin-1′-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-36)

Compound II-36 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 53N-(pyrimidin-2-ylmethyl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-37)

Compound II-37 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 468.1, M+H.

Example 54 (R)-tert-butylmethyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate(Compound II-38)

Compound II-38 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 55(R)-N-methyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-39)

Compound II-39 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 390.1, M+H.

Example 56 (S)-tert-butylmethyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate(Compound II-40)

Compound II-40 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 490.1, M+H.

Example 57(R)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-41)

Compound II-41 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 581-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)piperidin-4-yl)pyrrolidin-2-one(Compound II-42)

Compound II-42 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 59(S)-N-methyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-44)

Compound II-44 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 60(S)-N-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(Compound II-45)

Compound II-45 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 61(R)-N-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide(Compound II-46)

Compound II-46 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 62(R)-N-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)picolinamide(Compound II-47)

Compound II-47 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 63(S)-N,N-diethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-48)

Compound II-48 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 432.1, M+H.

Example 641-(naphthalen-1-yloxy)-3-((R)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylamino)propan-2-ol(Compound II-61)

Compound II-61 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 65(R)-N,N-diethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine(Compound II-49)

Compound II-49 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials.

Example 66N-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-10)

Compound II-10 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 398.1, M+H, analHPLC>98%; ¹H NMR (400 MHz; DMSO-d6) δ 8.51 (d, J=4.7 Hz, 1H); 8.20 (s,1H); 7.96-7.75 (m, 7H); 7.45 (d, J=7.8 Hz, 1H); 7.26 (m, 1H); 7.20 (d,J=8.2 Hz, 1H); 4.62 (s, 2H); 4.37 (m, 2H); 3.38 (m, 2H). ¹⁹F NMR (400MHz; DMSO-d6) δ −61.35 (s, 3F).

Example 67N-(cyclopropylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-11)

Compound II-11 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 361.1, M+H, analHPLC>98%; ¹H NMR (400 MHz; DMSO-d6) δ 8.51 (s, 1H); 8.15 (m, 3H); 8.07(m, 3H); 7.45 (d, J=8.3 Hz, 1H); 4.61 (s, 2H); 3.43 (m, 2H); 1.36 (m,1H); 0.71 (m, 2H); 0.49 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −60.96 (s,3F).

Example 68N-(pyridin-2-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-19)

Compound II-19 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 384.1, M+H, analHPLC>95%; ¹H NMR (400 MHz; DMSO-d6) δ 8.33 (d, J=4.7 Hz, 1H); 8.26 (s,1H); 8.12 (s, 1H); 7.92-7.80 (m, 6H); 7.70 (m, 1H); 7.20 (d, J=8.2 Hz,1H); 6.99 (m, 1H); 4.38 (m, 2H); 3.56 (m, 2H). ¹⁹F NMR (400 MHz;DMSO-d6) δ −61.37 (s, 3F).

Example 69N-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-20)

Compound II-20 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 428.1, M+H, analHPLC>95%; ¹H NMR (400 MHz; DMSO-d6) δ 8.26 (s, 1H); 8.13 (m, 1H);7.92-7.67 (m, 7H); 7.20 (d, J=8.6 Hz, 1H); 6.96 (m, 1H); 6.82 (d, J=8.6Hz, 1H); 4.48 (m, 2H); 4.40 (m, 2H); 3.69 (m, 2H); 3.43 (m, 2H). ¹⁹F NMR(400 MHz; DMSO-d6) δ −61.36 (s, 3F).

Example 70N-(2-phenoxyethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-22)

Compound II-22 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 427.1, M+H, analHPLC>95%; ¹H NMR (400 MHz; DMSO-d6) δ 8.16 (s, 1H); 7.93-7.79 (m, 6H);7.31-7.21 (m, 3H); 6.99-6.90 (m, 3H); 4.42 (m, 2H); 4.21 (m, 2H); 3.70(m, 2H); 3.50 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −61.36 (s, 3F).

Example 71N-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-33)

Compound II-33 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 451.1, M+H, analHPLC>98%; ¹H NMR (400 MHz; DMSO-d6) δ 10.53 (s, 1H); 8.11 (d, J=7.6 Hz,1H); 8.06 (s, 1H); 7.97 (m, 2H); 7.88 (m, 2H); 7.63 (m, 2H); 7.40 (m,1H); 7.31 (m, 1H); 7.24 (m, 2H); 5.06 (m, 2H); 4.51 (m, 2H); 3.86 (s,3H); 3.63 (m, 2H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −61.43 (s, 3F).

Example 72 tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate(Compound II-62)

Compound II-62 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 476.2, M+H, analHPLC>95%; ¹H NMR (400 MHz; DMSO-d6) δ 10.18 (m, 1H); 9.97 (m, 1H); 8.10(d, J=8.2 Hz, 1H); 7.97-7.95 (m, 5H); 7.36 (m, 1H); 4.48 (m, 2H); 4.34(m, 1H); 3.70 (m, 1H); 3.57 (m, 2H); 2.24 (m, 1H); 2.05 (m, 2H); 1.39(m, 9H). ¹⁹F NMR (400 MHz; DMSO-d6) δ −61.43 (s, 3F).

Example 73 (S)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate(Compound II-43)

Compound II-43 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 476.2, M+H, analHPLC>93%; ¹H NMR (400 MHz; DMSO-d6) δ 8.22 (s, 1H); 7.91 (m, 2H); 7.81(m, 3H); 7.73 (s, 1H); 7.16 (m, 1H); 4.36 (m, 3H); 3.58-3.20 (m, 7H);2.12 (m, 1H); 1.88 (m, 1H); 1.38 (m, 9H). ¹⁹F NMR (400 MHz; DMSO-d6) δ−61.36 (s, 3F).

Example 74 (R)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate(Compound II-63)

Compound II-63 was prepared according to Example 19 disclosed hereinusing the appropriate starting materials. MS m/z 476.2, M+H, analHPLC>95%; ¹H NMR (400 MHz; DMSO-d6) δ 8.23 (s, 1H); 7.91 (m, 2H); 7.81(m, 3H); 7.73 (s, 1H); 7.14 (m, 1H); 4.36 (m, 3H); 3.58-3.20 (m, 7H);2.12 (m, 1H); 1.88 (m, 1H); 1.38 (m, 9H). ¹⁹F NMR (400 MHz; DMSO-d6) δ−61.36 (s, 3F).

The following compounds were prepared according to the Examplesdisclosed herein using the appropriate starting materials:

3-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine(Compound I-4)

11-(4-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-2H-benzo[f]pyrimido[1,2-d][1,4]oxazepine(Compound I-8)

3-cyclopropyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-9)

2-(10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-3-yl)propan-2-ol(Compound I-10)

3-bromo-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-12)

3-chloro-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine(Compound I-13)

10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3-carbonitrile(Compound I-16)

ethyl10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate(Compound I-21)

10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylicacid (Compound I-22)

5-(3,3-difluoropyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine(Compound II-6)

N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine(Compound II-32)

Example 75

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

Example 76

A tablet Formula I is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

Example 77

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Example 78

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Example 79

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Example 80

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Example 81

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Example 82

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/mL Mannitol, USP 50 mg/mLGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0mL Nitrogen Gas, NF q.s.

Example 83

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients and water thenadded q.s. 100 g.

Example 84

Sustained Release Composition

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

The sustained release formulations of this disclosure are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate) andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma) and the like. These film-forming agents may optionally containcolorants, plasticizers and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Example 85

Activity testing is conducted in the Examples below using methodsdescribed herein and those well known in the art.

Sodium Current Screening Assays:

The late sodium current (Late INa) and peak sodium current (Peak INa)assays are performed on an automated electrophysiology platform, QPatch16× (Sophion Bioscience, Copenhagen, Denmark), which uses the whole cellpatch clamp technique to measure currents through the cell membrane ofup to 16 cells at a time. The assay uses an HEK293 (human embryonickidney) cell line heterologously expressing the wild-type human cardiacsodium channel, hNa_(v)1.5, purchased from Millipore (Billerica, Mass.).No beta subunits were coexpressed with the Na channel alpha subunit.Cells are maintained with standard tissue culture procedures and stablechannel expression is maintained with 400 μg/mL Geneticin in the culturemedium. Cells isolated for use on QPatch are incubated for 5 minutes inDetachin 1× (Genlantis, San Diego, USA) at 37° C. to ensure that 80-90%of the cells are single and not part of a cell cluster. Experiments arecarried out at 23-25° C.

For both the Late INa and Peak INa assays, series resistancecompensation is set to 100% and series resistance and whole-cellcompensation are performed automatically. Currents are digitized at 25kHz and low-pass filtered at 12 kHz and 10 kHz for the late and peak INaassays, respectively. Currents through open sodium channels areautomatically recorded and stored in the Sophion Bioscience Oracledatabase (Sophion Bioscience, Copenhagen, Denmark). Analysis isperformed using QPatch Assay and database software and data are compiledin Excel.

Compound stocks are routinely made by the Gilead Sample Bank in plasticvials to 10 mM in dimethyl sulfoxide (DMSO). In some cases, whencompounds are not soluble in DMSO, they are made in 100% ethanol. Stocksare sonicated as necessary. The extracellular solution for screeningLate INa is composed of: 140 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mMMgCl₂ and 5 mM HEPES with pH adjusted to 7.4 using NaOH. Theintracellular solution used to perfuse the inside of the cells for boththe Late INa and Peak INa assays contains: 120 mM CsF, 20 mM CsCl, 5 mMEGTA, 5 mM HEPES and pH adjusted to 7.4 with CsOH. Compounds are dilutedin extracellular solution to 1 μM in glass vials and then transferred toglass well plates before robotic addition to the cells. A 0 mM Naextracellular solution (ONa-ECF) is used at the end of each experimentfor the Late INa and Peak INa assays to measure baseline currentcontains: 140 mM N-methyl-D-glucamine; 4 mM KCl; 1.8 mM CaCl₂; 0.75 mMMgCl₂; 5 mM HEPES and pH was adjusted to 7.4 with HCl.

Late INa Screening Assay:

For the hNa_(v)1.5 Late INa assay, sodium channels are activated every10 seconds (0.1 Hz) by depolarizing the cell membrane to −20 mV for 250milliseconds (ms) from a holding potential of −120 mV. In response to a−20 mV voltage step, typical hNa_(v)1.5 sodium currents activate rapidlyto a peak negative current and then inactivate nearly completely within3-4 ms.

Compounds were tested to determine their activity in blocking the latesodium current. Late INa was generated by adding 10 μM Tefluthrin(pyrethroid) to the extracellular solution while recording Na currents.To confirm the block of late I_(Na) observed using the automatedscreening method, a second late I_(Na) enhancer (ATX-II) and the manualpatch clamp method were used. ATX-II and tefluthrin occupy distinct,non-overlapping binding sites and modify Na⁺ channel functiondifferently to increase late I_(Na). Compounds tested have been foundgenerally to inhibit the enhanced late I_(Na) caused by either lateI_(Na) enhancer. For the purposes of the screening, late INa is definedas the mean current between 225 ms and 250 ms after stepping to −20 mVto activate Na channels. After establishing the whole cell recordingconfiguration, late INa activator is added to each well 4 times over a16-17 minute period so that the late component of the Na current reachesa stable value. Compounds were then added (typically at 1 μM), in thepresence of the late INa activator, with 3 additions over the course of7 or 8 minutes. Measurements were made at the end of exposure to thethird compound addition and values were normalized to the current levelwhen all Na⁺ was removed from the extracellular solution after twoadditions of 0Na-ECF.

Results are reported as percent block of late INa. For example, whentested in the assay disclosed above with 10 μM Tefluthrin activatinglate INa, Compound II-105 inhibited (or reduced) the late sodium currentby 45% (see Table 1 for additional compound data). The inhibition ofLate INa of the cardiac isoform hNa_(v) 1.5 support the use of thecompounds of this disclosure to treat atrial arrhythmias, ventriculararrhythmias, heart failure (including congestive heart failure,diastolic heart failure, systolic heart failure, acute heart failure),Prinzmetal's (variant) angina, stable angina, unstable angina, exerciseinduced angina, congestive heart disease, ischemia, recurrent ischemia,reperfusion injury, myocardial infarction, acute coronary syndrome,peripheral arterial disease, pulmonary hypertension and intermittentclaudication.

Peak INa Screening Assay:

Compounds were also evaluated for their effect in several other assays,including their effect on hNa_(v)1.5 Peak INa. Good separation betweenthe concentrations of test compound to reduce late and peak I_(Na) isbeneficial to enable separation of the desired effect to reduce lateI_(Na)-induced electrical and mechanical dysfunction from the undesiredeffect to reduce peak I_(Na), which can lead to slowing or block ofconduction of electrical excitation in the heart. It is contemplatedthat the compounds of Formula I avoid significant block of peak INa.Since the peak INa in the cells used herein can be very large,introducing artifacts in the recording, the concentration of Na⁺ in thebath can be reduced to 20 mM and a nonpermeant cation added tocompensate for the Na⁺ that was removed to maintain the osmolarity andionic strength of the solution (see solution details below). Analysis ofpeak INa generally requires correction for rundown before determiningthe % block of peak current by the tested compound.

A separate Peak INa screening assay was developed to allow assessment ofthe effect of compounds on peak INa at both low and high stimulationfrequencies in order to identify compounds that are highly selective forblock of late INa but do not block peak INa. A low stimulation frequencyof 0.1 Hz was used to determine the effect of the test compound when thechannel spent most of the time in the resting (closed) state andprovides information about Tonic Block (TB). A higher stimulationfrequency (3 Hz) was used to measure block of the channel when it spentmore time in the activated and inactivated states and provided a measureof Use-Dependent Block (UDB). Use-dependent block refers to theaccumulation of block with increased frequency of channel activation.Block of cardiac peak I_(Na) by compounds of this disclosure isincreased with an increase in the frequency of stimulation from 0.1 to1-5 Hz (frequencies encountered either in the normal heart or duringtachycardia). It is therefore expected that reduction of peak I_(Na) bycompounds of this disclosure will be greater at high heart rates, suchas those during tachyarrhythmias, than at normal heart rates. As aconsequence, compounds of this disclosure may reduce Na⁺ and Ca²⁺overload due to late INa and abnormal electrical activity and electricalconduction in myocardium that is arrhythmic, especially during ischemia.

The −100 mV holding potential and the 3 Hz stimulation frequency werechosen so that the benchmark compound would have a small but detectableeffect under experimental conditions, allowing for direct comparison ofnew compounds with the benchmark. The extracellular solution forscreening Peak INa is composed of: 20 mM NaCl, 120 mM N-methyl-Dglucamine, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mM MgCl₂ and 5 mM HEPES with pHadjusted to 7.4 using HCl. The intracellular solution used for the PeakINa assay is the same as outlined for the Late INa assay (see above).

For the peak INa assay, Na⁺ channels were activated by depolarizing thecell membrane to 0 mV for 20 ms from a holding potential of −100 mV.After establishing the whole cell recording configuration, channels werestimulated to open with low frequency stimulation (0.1 Hz) for 7 minutesso that the recording can be monotered and the extent to which therecording has stabilized can be assessed. After this stabilizationperiod the stimulation frequency was increased to 3 Hz for 2 minutes andthen returned to 0.1 Hz. Since 3 Hz stimulation causes a small decreasein the peak current even in the absence of compound, this internalcontrol was used for each cell, when no compound is present, to correctthe results from 3 Hz stimulation when compound is present. Following 3Hz stimulation under control conditions, the cell is allowed to recoverfor 200 seconds before compound is added. The test compound tested at 1or 3 μM (depending on the % block of late INa at 1 μM) was added 3 timesat 60 second intervals, while stimulating the channels to open at 0.1 Hzto monitor the progression of TB. After the third compound addition, a320 second wait period was imposed to allow for equilibration before thesecond period of 3 Hz stimulation begins. TB was measured before thesecond period of 3 Hz stimulation. Both TB and UDB were analyzed byincorporating rundown correction for the peak INa and UDB as calculatedby compensating for the small use-dependent effect of the stimulationprotocol on peak INa in the absence of compound. Compound II-11exhibited peak INa TB of 11% and peak INa UDB of 31%, both measured at 1μM.

The above data demonstrates the selectivity of Compound II-11 to blocklate INa compared to peak INa (41% versus 11% for peak INa TB) whichsuggests compound II-11 should have minimal to no effect on electricalconduction through the heart (which is driven by peak INa) atconcentrations that effectively block late INa.

Compound II-11 inhibits peak INa UDB at 31% @ 1 μM. This suggests thatCompound II-11 may be useful at high heart rates, such as those duringtachyarrhythmias, than at normal heart rates. As a consequence,compounds of this disclosure may reduce Na⁺ and Ca²⁺ overload due tolate INa and abnormal electrical activity and electrical conduction inmyocardium that is arrhythmic, especially during ischemia.

TABLE 1 NAV1.1 NAV1.2 Late Peak Peak UDB- UDB- No. Name I_(Na)* TB* UDB*10 HZ* 10 HZ* I-1 10-(4-(trifluoromethyl)phenyl)-5,6- 32 −12 2dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine I-210-(4-(trifluoromethoxy)phenyl)-5,6- 31 1 18 dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-3 10-(4-(trifluoromethyl)phenyl)-5,6- 13dihydrobenzo[f][1,2,4]triazolo[4,3- d][1,4]oxazepine I-4 3-methyl-10-(4-10 (trifluoromethyl)phenyl)-5,6- dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine I-5 3-cyclopropyl-10-(4- 18(trifluoromethyl)phenyl)-5,6- dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine I-6 3-methyl-10-(4- 28 −10 −3(trifluoromethyl)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-7 3-(pyrimidin-2-yl)-10-(4- 17(trifluoromethyl)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-8 11-(4-(trifluoromethyl)phenyl)- 93,4,6,7-tetrahydro-2H- benzo[f]pyrimido[1,2- d][1,4]oxazepine I-93-cyclopropyl-10-(4- 4 4 0 (trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine I-102-(10-(4-(trifluoromethyl)phenyl)-5,6- 10 −5 0dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-3- yl)propan-2-ol I-113-benzyl-10-(4- 13 −5 −5 (trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine I-12 3-bromo-10-(4- 4 −7 6(trifluoromethyl)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-13 3-chloro-10-(4- 6 −3 8(trifluoromethyl)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-14 2-chloro-3-methyl-10-(4- 11 0 4(trifluoromethyl)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-15 1-(10-(4-(trifluoromethyl)phenyl)-5,6- 12dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepin-3- yl)ethanone I-1610-(4-(trifluoromethyl)phenyl)-5,6- 1 dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3- carbonitrile I-17 3-methyl-10-(4- 14(trifluoromethoxy)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-18 3-cyclopropyl-10-(4- 20(trifluoromethoxy)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-19 2-methyl-10-(4- 13 (trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine I-20 2-cyclopropyl-10-(4-12 (trifluoromethyl)phenyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine I-22 10-(4-(trifluoromethyl)phenyl)-5,6- 5dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine-2- carboxylic acid I-232-(1-methyl-1H-imidazol-5-yl)-10-(4- 3 (trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2- d][1,4]oxazepine II-1 5-morpholino-7-(4- 21(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepine II-2N-benzyl-7-(4- 41 27 57 9 24 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-3 5-(pyrrolidin-1-yl)-7-(4- 25(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepine II-4N-cyclopropyl-7-(4- 25 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-5 N-benzyl-N-methyl-7-(4- 28(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amine II-65-(3,3-difluoropyrrolidin-1-yl)-7-(4- 7 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-7 N-(pyrimidin-2-ylmethyl)-7-(4- 14(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amine II-8N-cyclopropyl-N-methyl-7-(4- 13 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-9 N-((3-fluoropyridin-2- 23yl)methyl)-7-(4- (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-10 N-(pyridin-2-ylmethyl)-7-(4-32 (trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amineII-11 N-(cyclopropylmethyl)-7-(4- 41 11 31 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-12 tert-butyl 1-(7-(4- 9(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)azetidin-3-ylcarbamate II-13 (S)-tert-butyl 1-(7-(4- 15(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-14 N-(2-(1H-imidazol-1-yl)ethyl)-7-(4-17 (trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amineII-15 (S)-N,N-dimethyl-1-(7-(4- 49 16 27 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-yl)pyrrolidin-3-amine II-16(S)-(1-(7-(4- 13 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-yl)pyrrolidin-3-yl)methanol II-17N-((1-methyl-1H-imidazol- 10 2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amineII-18 1-(7-(4-(trifluoromethyl)phenyl)-2,3- 9dihydrobenzo[f][1,4]oxazepin- 5-yl)azetidin-3-amine II-19N-(pyridin-2-yl)-7-(4- 43 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-20N-(2-(pyridin-2-yloxy)ethyl)-7-(4- 59 30 89(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amineII-21 5-(4,4-difluoropiperidin-1-yl)-7-(4- 13(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepine II-22N-(2-phenoxyethyl)-7-(4- 60 19 69 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-231-(7-(4-(trifluoromethyl)phenyl)-2,3- 9 dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ol II-24 N-(2-(2-chlorophenoxy)ethyl)-7-(4- 26(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amineII-25 7-(4-(trifluoromethyl)phenyl)-N- 20((6-(trifluoromethyl)pyridin-2- yl)methyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-26 N-(1H-tetrazol-5-yl)-7-(4-14 (trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amineII-27 7-(4-(trifluoromethyl)phenyl)-N- 1 (6-(trifluoromethyl)pyridin-2-yl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amine II-29N-(2,2,2-trifluoroethyl)-7-(4- 7 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-301-(7-(4-(trifluoromethyl)phenyl)-2,3- 10 dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-2-one II-31 5-(4-cyclopropylpiperazin-1-yl)-7-(4- 24(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepine II-32N-phenyl-7-(4- 26 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-33 N-((1-methyl-1H- 34benzo[d]imidazol-2- yl)methyl)-7-(4- (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-34 N-(1-(pyrimidin-2- 3ylmethyl)pyrrolidin-3-yl)-7-(4- (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-35 pyrimidin-2-yl(3-(7-(4- 4(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidin-1- yl)methanone II-365-(1,3′-bipyrrolidin-1′-yl)-7-(4- 7 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-37 N-(pyrimidin-2-ylmethyl)-1-(7-(4- 20(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-38 (R)-tert-butyl methyl(1-(7-(4- 18(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate II-39 (R)-N-methyl-1-(7-(4- 26(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-40 (S)-tert-butyl methyl(1-(7-(4- 18(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate II-41 (R)-1-(7-(4- 6(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-42 1-(1-(7-(4- 9(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)piperidin-4- yl)pyrrolidin-2-one II-43 (S)-tert-butyl 3-(7-(4- 4612 31 (trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine- 1-carboxylate II-44 (S)-N-methyl-1-(7-(4- 9(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-45 (S)-N-(1-(7-(4- 6(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)pyrimidine-2- carboxamide II-46 (R)-N-(1-(7-(4- 4(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)pyrimidine-2- carboxamide II-47 (R)-N-(1-(7-(4- 18(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)picolinamide II-48 (S)-N,N-diethyl-1-(7-(4- 24(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-49 (R)-N,N-diethyl-1-(7-(4- 11(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-50 (R)-tert-butyl 1-(7-(4- 22(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-51 (R)-N,N-dimethyl-1-(7-(4- 21(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-52 5-(4-methylpiperazin-1-yl)-7-(4- 10(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepine II-53(S)-tert-butyl 3-methyl-4-(7-(4- 2 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-yl)piperazine-1-carboxylate II-54N-phenyl-7-(4- 26 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-amine II-555-(3-morpholinopyrrolidin-1-yl)-7-(4- 18 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-56 (S)-1-(7-(4- 17(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine II-57 tert-butyl 1-(7-(4- 23(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate II-58 5-(2-(pyridin-2- 18yl)pyrrolidin-1-yl)-7-(4- (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine II-59 N-(pyrrolidin-3-yl)-7-(4- 8(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepin- 5-amineII-60 5-(3-(pyridin-2- 42 10 25 yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3- dihydrobenzo[f][1,4]oxazepine II-611-(naphthalen-1-yloxy)-3- 12 ((R)-1-(7-(4- (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-yl)pyrrolidin-3- ylamino)propan-2-olII-62 tert-butyl 3-(7-(4- 43 8 32 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-ylamino)pyrrolidine- 1-carboxylate II-63(R)-tert-butyl 3-(7-(4- 51 12 31 (trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin- 5-ylamino)pyrrolidine- 1-carboxylate *%Inhibition at 1 μM.

The assay results shown in the above Table establish that compoundstested showed activity as modulators of late sodium current, for exampleby inhibiting (or reducing) the late sodium current.

In some embodiments the effects of a compound of Formula I are specificfor the late sodium current and show little or no activity with respectto one or more other ion channels. Thus, in some embodiments, a compoundhaving an activity of reducing late sodium current will also exhibitlittle or no activity with regard to the peak sodium current.

Example 87 Expression of Human Na_(v)1.1 cDNA

All experiments with human Na_(v)1.1 are conducted as described (Kahlig,et al., PNAS. 2008, 105: 9799-9804). Briefly, expression of hNav1.1 isachieved by transient transfection using Qiagen Superfect reagent (5.5μg of DNA is transfected at a plasmid mass ratio of 10:1:1 forα₁:β₁:β₂). The human β₁ and β₂ cDNAs are cloned into plasmids containingthe marker genes DsRed (DsRed-IRES2-hβ₁) or eGFP (eGFP-IRES2-hβ₂)flanking an internal ribosome entry site (IRES).

Electrophysiology

Whole-cell voltage-clamp recordings are used to measure the biophysicalproperties of WT and mutant Na_(v)1.1 channels, as described previously(Kahlig, 2008). For recording hNav1.1 I_(Na), HEK293 cells aresuperfused with solution containing (in mM): 145 NaCl, 4 KCl, 1.8 CaCl₂,1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of 7.35 and osmolarity of 310mOsmol/kg. The pipette solution contains (in mM): 110 CsF, 10 NaF, 20CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 with an osmolarity of 300mOsmol/kg. Cells are allowed to stabilize for 10 min after establishmentof the whole-cell configuration before current is measured. Seriesresistance is compensated 90% to assure that the command potential isreached within microseconds with a voltage error <2 mV. Leak currentsare subtracted by using an online P/4 procedure and all currents arelow-pass Bessel filtered at 5 kHz and digitized at 50 kHz.

For use-dependent studies, cells are stimulated with depolarizing pulsetrains (−10 mV, 5 ms, 300 pulses, 10 and 25 Hz) from a holding potentialof −120 mV. Currents are then normalized to the peak current recorded inresponse to the first pulse in each frequency train. For tonic blockstudies, peak and persistent (late) currents are evaluated in responseto a 200 ms depolarization to −10 mV (0.2 Hz) following digitalsubtraction of currents recorded in the presence and absence of 0.5 μMtetrodotoxin (TTX). The sodium current termed Late INa in the peripheryis commonly called persistent INa in the CNS. Persistent current iscalculated during the final 10 ms of the 200 ms step. Data analysis isperformed using Clampfit 9.2 (Axon Instruments, Union City, Calif.,U.S.A), Excel 2002 (Microsoft, Seattle, Wash., U.S.A.), and OriginPro7.0 (OriginLab, Northampton, Mass., U.S.A) software. Results arepresented as mean±SEM.

In Vitro Pharmacology

A stock solution of 10 mM compound of Formula I is prepared in 0.1 M HClor DMSO. A fresh dilution of the compound of Formula I in the bathsolution is prepared every experimental day and the pH is readjusted to7.35 as necessary. The final DMSO concentration was kept at 0.1% in allsolutions. Direct application of the perfusion solution to the clampedcell is achieved using the Perfusion Pencil system (Automate, Berkeley,Calif.). Direct cell perfusion is driven by gravity at a flow rate of350 μL/min using a 250 micron tip. This system sequesters the clampedcell within a perfusion stream and enables complete solution exchangewithin 1 second. The clamped cell is perfused continuously startingimmediately after establishing the whole-cell configuration. Controlcurrents are measured during control solution perfusion. Whereappropriate, concentration inhibition curves are fit with the Hillequation: I/I_(max)=1/[1+10̂(log IC₅₀−I)*k], where IC₅₀ is theconcentration that produces half inhibition and k is the Hill slopefactor.

Solutions containing the compounds of the disclosure are perfused forthree minutes prior to current recordings to allow equilibrium (tonic)drug block. Tonic block of peak current is measured from thissteady-state condition. Use-dependent block of peak current is measuredduring pulse number 300 of the pulse train, (−10 mV, 5 ms, 300 pulses,10 Hz) from a holding potential of −120 mV. Two sequential pulse trainstimulations are averaged to obtain mean current traces for eachrecording condition.

In Vivo Pharmacology

Jugular vein cannulated male Sprague Dawley rats (250-350 g, CharlesRiver Laboratories, Hollister, Calif.) are used to study brainpenetration of the compounds of the disclosure in vivo. Animal use isapproved by the Institutional Animal Care and Use Committee, GileadSciences. Three rats per group are infused intravenously with thecompound of the disclosure in saline at 85.5 μg/kg/min. After 1, 2.5 or5 h the animals are sacrificed for plasma and brain collection, andconcentrations of the compound of the disclosure are measured by liquidchromatography coupled with tandem mass spectrometry (LC-MS/MS). Braintissue is homogenated in 1% 2N HCl acidified 5% sodium fluoride (finalhomogenate is diluted 3-fold). Plasma and brain homogenate samples (50μl) are precipitated along with deuterated D3-Formula I as an internalstandard, vortexed and centrifuged. The supernatant (50 μL) istransferred and diluted with water (450 μl) prior to injection (10 μl).High performance liquid chromatography was performed using a ShimadzuLC-10AD liquid chromatograph and a Luna C18(2), 3 μm, 20×2.0 mm columnwith a mobile phase consisting of water containing 0.1% formic acid(solution A) and acetonitrile (solution B) carried out under isocraticconditions (75% solution A, 25% solution B; flow rate 0.300 ml/min).Mass spectrometric analyses are performed using an API3000 massspectrometer (Applied Biosystems, Foster City, Calif.) operating inpositive ion mode with MRM transition 428.1>98. Brain-to-plasma ratiosare calculated for each sample as ng compound/g brain divided by ngcompound/ml plasma.

The compound of Example 1-2 blocked the Nav1.1 channel current by 1%under Chantest conditions at 10 Hz at 1 μM.

Example 88 Expression of Human Na_(v)1.2 cDNA

Wild-type (WT) cDNA stably transfected in Chinese hamster ovary (CHO)cells is used to record I_(Na). Unless otherwise noted, all reagents arepurchased from Sigma-Aldrich (St Louis, Mo., U.S.A.).

Electrophysiology

Whole-cell voltage-clamp recordings are used to measure the biophysicalproperties of WT. Briefly, the pipette solution consists of (in mM) 110CsF, 10 NaF, 20 CsCl, 2 EGTA, 10 HEPES, with a pH of 7.35 and osmolarityof 300 mOsmol/kg. The bath (control) solution contains in (mM): 145NaCl, 4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 dextrose, 10 HEPES, with a pH of7.35 and osmolarity of 310 mOsmol/kg. Cells are allowed to stabilize for10 min after establishment of the whole-cell configuration beforecurrent is measured. Series resistance is compensated 90% to assure thatthe command potential is reached within microseconds with a voltageerror <2 mV. Leak currents are subtracted by using an online P/4procedure and all currents are low-pass Bessel filtered at 5 kHz anddigitized at 50 kHz.

For clarity, representative ramp currents are low pass filtered off-lineat 50 Hz. Specific voltage-clamp protocols assessing channel activation,fast inactivation and availability during repetitive stimulation areused. Results are presented as mean±SEM.

Tonic block of peak current is measured using a step to −10 mV (20 ms)from a holding potential of −120 mV (0.2 Hz). Use-dependent block ofpeak current is measured during pulse number 300 of a pulse train (−10mV, 5 ms, 300 pulses, 10 Hz or 25 Hz) from a holding potential of −120mV. Currents are then normalized to the peak current recorded inresponse to the first pulse in each frequency train. For tonic blockstudies, peak current is evaluated in response to a 20 ms depolarizationto −10 mV (0.2 Hz). Two sequential pulse train stimulations are averagedto obtain mean current traces for each recording condition, which arethen used for offline subtraction and analysis.

Data analysis is performed using Clampfit 9.2 (Axon Instruments, UnionCity, Calif., U.S.A), Excel 2002 (Microsoft, Seattle, Wash., U.S.A.),and OriginPro 7.0 (OriginLab, Northampton, Mass., U.S.A) software.Results are presented as mean±SEM.

In Vitro Pharmacology

A stock solution of 10 mM compound of Formula I is prepared in 0.1 M HClor DMSO. A fresh dilution of the compound of Formula I in the bathsolution is prepared every experimental day and the pH is readjusted to7.35 as necessary. The final DMSO concentration was kept at 0.1% in allsolutions. Direct application of the perfusion solution to the clampedcell is achieved using the Perfusion Pencil system (Automate, Berkeley,Calif.). Direct cell perfusion is driven by gravity at a flow rate of350 μL/min using a 250 micron tip. This system sequesters the clampedcell within a perfusion stream and enables complete solution exchangewithin 1 second. The clamped cell is perfused continuously startingimmediately after establishing the whole-cell configuration. Controlcurrents are measured during control solution perfusion.

Solutions are perfused for three minutes prior to current recordings toallow equilibrium (tonic) drug block. Tonic block of peak currents ismeasured from this steady-state condition. Three sequential currenttraces are averaged to obtain a mean current for each recording. Themean current traces are utilized for offline analysis. Whereappropriate, concentration inhibition curves are fit with the Hillequation: I/I_(max)=1/[1+10̂(log IC₅₀−I)*k], where IC₅₀ is theconcentration that produces half inhibition and k is the Hill slopefactor.

Using the above methods it may be demonstrated that the compounds of thedisclosure are selective for inhibiting cardiac Late INa current withoutinhibiting peak and low frequency currents of brain isoforms Na_(v)1.1and Na_(v)1.2. The compounds of the disclosure may inhibit the very highfrequency firing of Na_(v)1.1 and Na_(v)1.2 or demonstrate voltagedependent block of mutant Na_(v)1.1 and Na_(v)1.2 observed with epilepsypatients. In addition compounds of this disclosure may show activity forinhibition of a panel of Na_(v)1.1 mutant channels associated with theepilepsy and headache (migraine) syndromes GEFS+, SMEI and FHM3suggesting the ability of the compounds of the disclosure topreferentially block the abnormal increased persistent current carriedby these mutant channels.

When tested in the assay disclosed above for hNa_(v)1.2 sodium channelisoforms, the compound of Example 1-2 blocked the Nav1.2 channel currentby 18% under Chantest conditions at 10 Hz at 1 μM. The inhibition ofeither hNa_(v)1.1 and hNa_(v)1.2 isoforms or the inhibition of bothchannels when stimulated at these frequencies support the use ofcompounds of this disclosure to treat patients with epilepsy.

1. A compound of Formula I:

wherein: —Y—Z— is —C(═NR⁴)—NR²— or —C(NR⁵R⁶)═N—; R¹ is aryl, cycloalkyl,cycloalkenyl, heterocyclyl or heteroaryl; wherein said aryl, cycloalkyl,cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted withone, two or three substituents independently selected from the groupconsisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,—C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,—N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰,—S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl,aryl, heteroaryl and heterocyclyl; and wherein said C₁₋₆ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl areoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, phenyl, heterocyclyl,heteroaryl, C₁₋₆ alkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; R² is hydrogen, C₁₋₆ alkyl,—C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(═O)₂— R²⁰,cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl,aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰; wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, S(O)₂—R²⁰ and —O—R²⁰; n is 0, 1, 2,3 or 4; each R³ is independently C₁₋₆ alkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; wherein said cycloalkyl, aryl, heterocyclyl or heteroarylare optionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl, are optionally further substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and—O—R²⁰; or two R³ attached to a common carbon atom form an oxo; or twoR³ attached to a common or adjacent carbon atoms form a cycloalkyl orheterocyclyl; wherein said cycloalkyl or heterocyclyl are optionallyfurther substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; R⁴ is C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; wherein said cycloalkyl, aryl, heterocyclyl or heteroarylare optionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; or R² and R⁴ can join together withthe atom to which they are attached to form a heterocyclyl orheteroaryl; wherein said heterocyclyl or heteroaryl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, C₁₋₆ alkyl, cycloalkyl, heteroaryl,—CN, —O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰;and wherein said C₁₋₆ alkyl or heteroaryl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl;R⁵ is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl; wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),—C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; wherein saidcycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl areoptionally further substituted with one, two or three substituentsindependently selected from the group consisting of hydroxyl, halo,—NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰; R⁶ is C₁₋₆ alkyl, cycloalkyl,aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl, cycloalkyl,aryl, heteroaryl or heterocyclyl are optionally substituted with one,two or three substituents independently selected from the groupconsisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰; or R⁵ and R⁶can join together with the atom to which they are attached to form aheterocyclyl or heteroaryl; wherein said heterocyclyl or heteroaryl isoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, C₁₋₆ alkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, —CN, oxo, —O—R²⁰, —N(R²⁰)(R²²),—N(R²⁰)—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and wherein saidC₁₋₆ alkyl or heterocyclyl is optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo, oxo, heteroaryl and —O—R²⁰; R²⁰ and R²² are in each instanceindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and wherein theC₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of hydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo,—NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, aryloxy, —CF₃, —OCF₃, —OCH₂CF₃,—C(O)—NH₂, aryl, cycloalkyl and heteroaryl; wherein said heteroaryl isoptionally further substituted with C₁₋₄ alkyl or cycloalkyl; or whenR²⁰ and R²² are attached to a common nitrogen atom R²⁰ and R²² may jointo form a heterocyclyl or heteroaryl which is then optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of hydroxyl, halo, C₁₋₄ alkyl, aralkyl,aryloxy, aralkyloxy, acylamino, —NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃,—OCF₃, aryl, heteroaryl and cycloalkyl; each R²⁶ is independentlyselected from the group consisting of hydrogen, C₁₋₄ alkyl, aryl andcycloalkyl; and wherein the C₁₋₄ alkyl, aryl and cycloalkyl may befurther substituted with from 1 to 3 substituents independently selectedfrom the group consisting of hydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and—OCF₃; or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or tautomer thereof; provided that when R² and R⁴ jointogether with the atom to which they are attached to form an optionallysubstituted imidazolyl, the imidazolyl it is not directly substitutedwith an optionally substituted triazolyl, or R¹ is not optionallysubstituted pyrazolyl, 2-pyridinonyl or 2-fluoropyridinyl.
 2. Thecompound of Formula I represented by Formula IA:

wherein: R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl orheteroaryl; wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl orheteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰,—N(R²⁰)(R²²), C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,—N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²),C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl; and wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆alkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; R² is hydrogen, C₁₋₆ alkyl,—C(O)—R²⁰, —C(O)—OR²⁶, —C(O)—N(R²⁶)(R²⁶), —N(R²⁰)—S(═O)₂— R²⁰,cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, halo, —NO₂, cycloalkyl,aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN, oxo and —O—R²⁰; wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, —CF₃, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN, S(O)₂—R²⁰ and —O—R²⁰; n is 0, 1, 2,3 or 4; each R³ is independently C₁₋₆ alkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; wherein said cycloalkyl, aryl, heterocyclyl or heteroarylare optionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl, are optionally further substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and—O—R²⁰; or two R³ attached to a common carbon atom form an oxo; or twoR³ attached to a common or adjacent carbon atoms form a cycloalkyl orheterocyclyl; wherein said cycloalkyl or heterocyclyl are optionallyfurther substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; R⁴ is C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; wherein said cycloalkyl, aryl, heterocyclyl or heteroarylare optionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; or R² and R⁴ can join together withthe atom to which they are attached to form a heterocyclyl orheteroaryl; wherein said heterocyclyl or heteroaryl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, C₁₋₆ alkyl, cycloalkyl, heteroaryl,—CN, —O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰;and wherein said C₁₋₆ alkyl or heteroaryl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl;R²⁰ and R²² are in each instance independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl; and wherein the C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryland heteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —SO₂R²⁶, —CN, C₁₋₃alkoxy, aryloxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl, cycloalkyl andheteroaryl; wherein said heteroaryl is optionally further substitutedwith C₁₋₄ alkyl or cycloalkyl; or when R²⁰ and R²² are attached to acommon nitrogen atom R²⁰ and R²² may join to form a heterocyclyl orheteroaryl which is then optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino,—NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl andcycloalkyl; each R²⁶ is independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; and wherein the C₁₋₄alkyl, aryl and cycloalkyl may be further substituted with from 1 to 3substituents independently selected from the group consisting ofhydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃; or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers, or tautomerthereof; provided that when R² and R⁴ join together with the atom towhich they are attached to form an optionally substituted imidazolyl,the imidazolyl it is not directly substituted with an optionallysubstituted triazolyl, or R¹ is not optionally substituted pyrazolyl,2-pyridinonyl or 2-fluoropyridinyl.
 3. The compound of claim 2, wherein:R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroaryl;wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl or heteroarylare optionally substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, —CN,—SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²),C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,—N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²),C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl; and wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆alkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; n is 0; and R² and R⁴ join togetherwith the atom to which they are attached to form a heterocyclyl orheteroaryl; wherein said heterocyclyl or heteroaryl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, C₁₋₆ alkyl, cycloalkyl, heteroaryl,—CN, —O—R²⁰, —N(R²⁰)(R²²), —C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰;and wherein said C₁₋₆ alkyl or heteroaryl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.4. The compound of claim 2, wherein: R¹ is aryl; wherein said aryl isoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃,—O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), C(O)—N(R²⁰)(R²²),—N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰,—O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl; and wherein saidC₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl orheterocyclyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆ alkyl, cycloalkyl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;n is 0; and R² and R⁴ join together with the atom to which they areattached to form a heterocyclyl or heteroaryl; wherein said heterocyclylor heteroaryl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,C₁₋₆ alkyl, cycloalkyl, heteroaryl, —CN, —O—R²⁰, —N(R²⁰)(R²²),—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and wherein said C₁₋₆ alkylor heteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.
 5. The compound of claim2, wherein: R¹ is aryl optionally substituted with —O—R²⁰ or C₁₋₆ alkyl;and wherein said C₁₋₆ alkyl is optionally substituted with one, two orthree halo; n is 0; R² and R⁴ join together with the atom to which theyare attached to form a heterocyclyl or heteroaryl; wherein saidheterocyclyl or heteroaryl is optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo, C₁₋₆ alkyl, cycloalkyl, heteroaryl, —CN, —O—R²⁰, —N(R²⁰)(R²²),—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and wherein said C₁₋₆ alkylor heteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.
 6. The compound of claim2, wherein: R¹ is phenyl substituted with —O—CF₃ or —CF₃; n is 0; and R²and R⁴ join together with the atom to which they are attached to form aheterocyclyl or heteroaryl; wherein said heterocyclyl or heteroaryl isoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, C₁₋₆ alkyl, cycloalkyl,heteroaryl, —CN, —C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; andwherein said C₁₋₆ alkyl or heteroaryl are optionally substituted withone, two or three substituents independently selected from the groupconsisting of halo, —CN, —O—R²⁰, C₁₋₆ alkyl, aryl, and heteroaryl.
 7. Acompound selected from the group consisting of: I-53-cyclopropyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine; I-63-methyl-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine; I-73-(pyrimidin-2-yl)-10-(4-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine; and I-183-cyclopropyl-10-(4-(trifluoromethoxy)phenyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine;

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or tautomer, thereof.
 8. The compound of Formula Irepresented by Formula IB:

wherein: R¹ is aryl, cycloalkyl, cycloalkenyl, heterocyclyl orheteroaryl; wherein said aryl, cycloalkyl, cycloalkenyl, heterocyclyl orheteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰,—N(R²⁰)(R²²), C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,—N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²),C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl; and wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆alkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; n is 0, 1, 2, 3 or 4; each R³ isindependently C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;wherein said C₁₋₆ alkyl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),—C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; wherein saidcycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, areoptionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;or two R³ attached to a common carbon atom form an oxo; or two R³attached to a common or adjacent carbon atoms form a cycloalkyl orheterocyclyl; wherein said cycloalkyl or heterocyclyl are optionallyfurther substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; R⁵ is C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —NO₂, cycloalkyl, aryl, heterocyclyl,heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CNand —O—R²⁰; wherein said cycloalkyl, aryl, heterocyclyl or heteroarylare optionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰; R⁶ is C₁₋₆alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein said C₁₋₆alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; wherein said C₁₋₆ alkyl, cycloalkyl,aryl, heterocyclyl or heteroaryl are optionally further substituted withone, two or three substituents independently selected from the groupconsisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl or heteroaryl are optionally furthersubstituted with one, two or three substituents independently selectedfrom the group consisting of hydroxyl, halo, —NO₂, —N(R²⁰)(R²²),—C(O)—R²⁰, —C(O)—OR²⁰; or R⁵ and R⁶ can join together with the atom towhich they are attached to form a heterocyclyl or heteroaryl; whereinsaid heterocyclyl or heteroaryl is optionally substituted with one, twoor three substituents independently selected from the group consistingof halo, C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN,oxo, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and—C(O)—OR²⁰; and wherein said C₁₋₆ alkyl or heterocyclyl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, oxo, heteroaryl and —O—R²⁰; R²⁰ andR²² are in each instance independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl; and wherein the C₁₋₆ alkyl, cycloalkyl, heterocyclyl, aryland heteroaryl are optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, C₁₋₄ alkyl, acylamino, oxo, —NO₂, —SO₂R²⁶, —CN, C₁₋₃alkoxy, aryloxy, —CF₃, —OCF₃, —OCH₂CF₃, —C(O)—NH₂, aryl, cycloalkyl andheteroaryl; wherein said heteroaryl is optionally further substitutedwith C₁₋₄ alkyl or cycloalkyl; or when R²⁰ and R²² are attached to acommon nitrogen atom R²⁰ and R²² may join to form a heterocyclyl orheteroaryl which is then optionally substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, C₁₋₄ alkyl, aralkyl, aryloxy, aralkyloxy, acylamino,—NO₂, —SO₂R²⁶, —CN, C₁₋₃ alkoxy, —CF₃, —OCF₃, aryl, heteroaryl andcycloalkyl; and each R²⁶ is independently selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, aryl and cycloalkyl; wherein theC₁₋₄ alkyl, aryl and cycloalkyl may be further substituted with from 1to 3 substituents independently selected from the group consisting ofhydroxyl, halo, C₁₋₄ alkoxy, —CF₃ and —OCF₃; or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers, or tautomerthereof.
 9. The compound of claim 8, wherein: R¹ is aryl, cycloalkyl,cycloalkenyl, heterocyclyl or heteroaryl; wherein said aryl, cycloalkyl,cycloalkenyl, heterocyclyl or heteroaryl are optionally substituted withone, two or three substituents independently selected from the groupconsisting of halo, —NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰,—C(O)—R²⁰, —C(O)—OR²⁰, —N(R²⁰)(R²²), C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²²,—N(R²⁰)—C(O)—OR²², —N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰,—S(═O)₂—N(R²⁰)(R²²), C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl,aryl, heteroaryl and heterocyclyl; and wherein said C₁₋₆ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl areoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, phenyl, heterocyclyl,heteroaryl, C₁₋₆ alkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; n is 0; R⁵ is hydrogen, C₁₋₆ alkyl;and R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclylare optionally substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),—C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; wherein saidC₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionallyfurther substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl areoptionally further substituted with one, two or three substituentsindependently selected from the group consisting of hydroxyl, halo,—NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰; or R⁵ and R⁶ can jointogether with the atom to which they are attached to form a heterocyclylor heteroaryl; wherein said heterocyclyl or heteroaryl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, C₁₋₆ alkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, —CN, oxo, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰,—N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and wherein said C₁₋₆ alkyl orheterocyclyl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,oxo, heteroaryl and —O—R²⁰.
 10. The compound of claim 8, wherein: R¹ isaryl; wherein said aryl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, —CN, —SF₅, —Si(CH₃)₃, —O—R²⁰, —S—R²⁰, —C(O)—R²⁰, —C(O)—OR²⁰,—N(R²⁰)(R²²), C(O)—N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²², —N(R²⁰)—C(O)—OR²²,—N(R²⁰)—S(═O)₂—R²⁶, —S(═O)₂—R²⁰, —O—S(═O)₂—R²⁰, —S(═O)₂—N(R²⁰)(R²²),C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl; and wherein said C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substitutedwith one, two or three substituents independently selected from thegroup consisting of halo, —NO₂, phenyl, heterocyclyl, heteroaryl, C₁₋₆alkyl, cycloalkyl, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰,—C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; n is 0; R⁵ is hydrogen, C₁₋₆ alkyl;and R⁶ is C₁₋₁₅ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl or heterocyclylare optionally substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²),—C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; wherein saidC₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl are optionallyfurther substituted with one, two or three substituents independentlyselected from the group consisting of halo, —NO₂, C₁₋₆ alkyl, aralkyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, —N(R²⁰)(R²²), —C(O)—R²⁰,—C(O)—OR²⁰, C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰; and wherein said C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl areoptionally further substituted with one, two or three substituentsindependently selected from the group consisting of hydroxyl, halo,—NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰; or R⁵ and R⁶ can jointogether with the atom to which they are attached to form a heterocyclylor heteroaryl; wherein said heterocyclyl or heteroaryl is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halo, C₁₋₆ alkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, —CN, oxo, —O—R²⁰, —N(R²⁰)(R²²), —N(R²⁰)—C(O)—R²⁰,—N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and wherein said C₁₋₆ alkyl orheterocyclyl is optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,oxo, heteroaryl and —O—R²⁰.
 11. The compound of claim 8, wherein: R¹ isaryl optionally substituted with —O—R²⁰ or C₁₋₆ alkyl; and wherein saidC₁₋₆ alkyl is optionally substituted with one, two or three halo; n is0; R⁵ is hydrogen or C₁₋₆ alkyl; and R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl; wherein said C₁₋₆ alkyl, cycloalkyl, aryl,heteroaryl or heterocyclyl are optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo, —NO₂, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰,wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroarylare optionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰; or R⁵ and R⁶can join together with the atom to which they are attached to form aheterocyclyl or heteroaryl; wherein said heterocyclyl or heteroaryl isoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, C₁₋₆ alkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, oxo, —CN, —O—R²⁰, —N(R²⁰)(R²²),—N(R²⁰)—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and wherein saidC₁₋₆ alkyl or heterocyclyl is optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo, oxo, heteroaryl and —O—R²⁰.
 12. The compound of claim 8, wherein:R¹ is phenyl substituted with —O—CF₃ or —CF₃; n is 0; R⁵ is hydrogen orC₁₋₆ alkyl; and R⁶ is C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl; wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl are optionally substituted with one, two or threesubstituents independently selected from the group consisting of halo,—NO₂, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;wherein said C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl or heteroarylare optionally further substituted with one, two or three substituentsindependently selected from the group consisting of halo, —NO₂, C₁₋₆alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,—N(R²⁰)(R²²), —C(O)—R²⁰, —C(O)—OR²⁰, —C(O)—N(R²⁰)(R²²), —CN and —O—R²⁰;and wherein said C₁₋₆ alkyl, aralkyl, cycloalkyl, aryl, heterocyclyl orheteroaryl are optionally further substituted with one, two or threesubstituents independently selected from the group consisting ofhydroxyl, halo, —NO₂, —N(R²⁰)(R²²), —C(O)—R²⁰, C(O)—OR²⁰; or R⁵ and R⁶can join together with the atom to which they are attached to form aheterocyclyl or heteroaryl; wherein said heterocyclyl or heteroaryl isoptionally substituted with one, two or three substituents independentlyselected from the group consisting of halo, C₁₋₆ alkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, oxo, —CN, —O—R²⁰, —N(R²⁰)(R²²),—N(R²⁰)—C(O)—R²⁰, —N(R²⁰)—C(O)—OR²⁰ and —C(O)—OR²⁰; and wherein saidC₁₋₆ alkyl or heterocyclyl is optionally substituted with one, two orthree substituents independently selected from the group consisting ofhalo, oxo, heteroaryl and —O—R²⁰.
 13. The compound of claim 8 whereinthe groups R⁵ and R⁶ combine with the nitrogen atom to which they areattached to form a heterocyclyl group selected from the group consistingof

wherein the point of attachment to the oxazepine ring is at the bivalentnitrogen atom as drawn.
 14. The compound of claim 1 wherein R² and R⁴join together with the atom to which they are attached to form aheterocyclyl or heteroaryl selected from the group consisting of

wherein the broken lines denote the points of attachment to theoxazepine ring to form a tricyclic group.
 15. A compound selected fromthe group consisting of: II-15-morpholino-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine;II-2N-benzyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine;II-35-(pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine;II-4N-cyclopropyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-5 N-benzyl-N-methyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-9N-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-10N-(pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-11N-(cyclopropylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-13 (S)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate; II-14N-(2-(1H-imidazol-1-yl)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-15(S)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine; II-19N-(pyridin-2-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-20N-(2-(pyridin-2-yloxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-22N-(2-phenoxyethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-24N-(2-(2-chlorophenoxy)ethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-257-(4-(trifluoromethyl)phenyl)-N-((6-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-315-(4-cyclopropylpiperazin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine; II-32N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine;II-33N-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine; II-37N-(pyrimidin-2-ylmethyl)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine; II-38(R)-tert-butyl methyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate; II-39(R)-N-methyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine; II-40(S)-tert-butylmethyl(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)carbamate; II-43(S)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate; II-47(R)-N-(1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-yl)picolinamide; II-48(S)-N,N-diethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine; II-50(R)-tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate; II-51(R)-N,N-dimethyl-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine; II-54N-phenyl-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine;II-55 5-(3-morpholinopyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine; II-56(S)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-amine; II-57 tert-butyl1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylcarbamate; II-585-(2-(pyridin-2-yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine; II-605-(3-(pyridin-2-yl)pyrrolidin-1-yl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine; II-611-(naphthalen-1-yloxy)-3-((R)-1-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-yl)pyrrolidin-3-ylamino)propan-2-ol;II-62 tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate; and II-63 (R)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylate;

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or tautomer thereof. 16.-17. (canceled)
 18. The compoundN-(cyclopropylmethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-amineor a pharmaceutically acceptable salt thereof.
 19. The compound(R)-tert-butyl3-(7-(4-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepin-5-ylamino)pyrrolidine-1-carboxylateor a pharmaceutically acceptable salt thereof.
 20. A method of treatinga disease state in a mammal that is alleviable by treatment with anagent capable of reducing late sodium current, comprising administeringto a mammal in need thereof a therapeutically effective dose of acompound of claim
 1. 21. The method of claim 20, wherein the diseasestate is a cardiovascular disease selected from one or more of atrialand ventricular arrhythmias, heart failure (including congestive heartfailure, diastolic heart failure, systolic heart failure, acute heartfailure), Prinzmetal's (variant) angina, stable and unstable angina,exercise induced angina, congestive heart disease, ischemia, recurrentischemia, reperfusion injury, myocardial infarction, acute coronarysyndrome, peripheral arterial disease, pulmonary hypertension, andintermittent claudication.
 22. The method of 21, wherein the diseasestate is diabetes or diabetic peripheral neuropathy.
 23. The method of22, wherein the disease state results in one or more of neuropathicpain, epilepsy, seizures, headache or paralysis.
 24. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof. 25.-26. (canceled)